allopurinol and Body-Weight

Uric acid is a strong scavenger of reactive oxygen species, which are known to contribute to the development of atherosclerosis, while the incidence of atherosclerotic diseases is rather high in patients with gout. Among the established risk factors for atherosclerosis, oxidized LDL is believed to play a major role in its development and progression. Allopurinol and its active metabolite, oxypurinol, have been suggested to possess an antioxidant ability to scavenge the hydroxyl radical. Therefore, allopurinol may be beneficial in the prevention of LDL oxidation, as well as in the treatment of hyperuricemia. The objective of this work was to determine the degree of LDL oxidation in gout and the effect of allopurinol on LDL oxidation.. Age-matched male patients with primary intercritical gout and healthy male adults were included in the study. The serum concentrations of oxidized LDL autoantibodies and total antioxidant status were measured using an enzyme immunoassay.. Serum concentrations of oxidized LDL autoantibodies were significantly higher in patients with gout than the control subjects (p < 0.05) and were significantly decreased after allopurinol treatment (p < 0.05), but not by benzbromarone treatment, in spite of the similar concentrations of uric acid and total antioxidant status in serum following their separate administration.. Although the exact mechanism remains unclear, increased serum concentrations of oxidized LDL may play a role in the high incidence of coronary artery disease in gout. In addition, allopurinol may be more preferable to benzbromarone for treatment of gout in light of its inhibitory action toward LDL oxidation.

Topics: Allopurinol; Antioxidants; Autoantibodies; Body Weight; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Gout; Humans; Lipoproteins, LDL; Male; Middle Aged; Smoking; Triglycerides; Uric Acid

The purpose of the present study was to evaluate the efficacy of the treatment with a recombinant cysteine proteinase from Leishmania, rldccys1, associated with allopurinol or miltefosine on Leishmania (Leishmania) infantum chagasi-infected hamsters. Golden Syrian hamsters infected with L. (L.) infantum chagasi were treated with either miltefosine (46 mg/kg) or allopurinol (460 mg/kg) alone by oral route or associated with rldccys1 (150 µg/hamster) by subcutaneous route for 30 days. Infected hamsters were also treated with miltefosine (46 mg/kg) plus rldccys1 (150 µg/hamster) for 30 days (phase 1) followed by two additional doses of rldccys1 (250 µg/hamster) (phase 2). After the end of treatment, the animals were analyzed for parasite load, body weight, serum levels of immunoglobulins, cytokine expression, and drug toxicity. The data showed a significant decrease of parasite load in infected hamsters treated with allopurinol or miltefosine alone or associated with rldccys1, as well as in those treated with rldccys1 alone. Significantly lower levels of serum IgG were detected in hamsters treated with allopurinol plus rldccys1. The treatment with miltefosine associated with rldccys1 prevented relapse observed in animals treated with miltefosine alone. A significant loss of body weight was detected only in some hamsters treated with miltefosine for 1 month and deprived of this treatment for 15 days. There were no significant differences in transcript expression of IFN-γ and IL-10 in any of treated groups. Neither hepatotoxicity nor nephrotoxicity was observed among controls and treated groups. These findings open perspectives to further explore this immunochemotherapeutic schedule as an alternative for treatment of visceral leishmaniasis.

Topics: Allopurinol; Animals; Antiprotozoal Agents; Body Weight; Cricetinae; Leishmania infantum; Leishmaniasis, Visceral; Mesocricetus; Phosphorylcholine

To study the protective effect of electroacupuncture (EA) at "Biao"-acupoints, "Fenglong"(ST40) and "Zhongwan"(CV12), used for treating symptoms of the disease, and "Ben"-acupoints, "Zusanli"(ST36) and "Guanyuan"(CV4), for treating the root cause of the disease on oxidative stress injury of renal mitochondria through SIRT1/PGC-1α signal pathway in rats with diabetic nephropathy (DN).. Compared with the normal group, the levels of FBG, HbA1c, BUN, Scr, 24-h UP, TG, TC, LDL-C, MDA, α-SMA, Col Ⅰ, Col Ⅳ and FN proteins were significantly increased (. EA of ST36-ST40 and CV4-CV12, "Biao-Ben" acupoints combination, can alleviate oxidative stress and mitochondrial dysfunction in DN rats, which may be associated with its functions in up-regulating SIRT1/PGC-1α signaling, and decreasing renal fibrosis.

Topics: Actins; Acupuncture Points; Animals; Blood Glucose; Body Weight; Catalase; Cholesterol, HDL; Cholesterol, LDL; Collagen; Creatinine; Diabetic Nephropathies; Electroacupuncture; Eosine Yellowish-(YS); Fibronectins; Glutathione; Glycated Hemoglobin; Hematoxylin; Male; Malondialdehyde; Mitochondria; Nitrogen; Obesity; Rats; Rats, Wistar; Sirtuin 1; Streptozocin; Superoxide Dismutase; Triglycerides; Urease; Xanthine Oxidase

Recent studies highlighted the association of hyperuricemia and metabolic syndrome (MS). The aim of this study was to compare the beneficial effects of febuxostat versus allopurinol on the biochemical changes that occur in MS.. Forty adult male Sprague Dawley albino rats were used in the study. Insulin resistance and MS were induced by administration of a high-fructose diet for 8 weeks. Follow-up of changes in weight, blood pressure, serum biochemical parameters, serum antioxidant catalase, and glutathione peroxidase activities was done. At the end of the study, animals were sacrificed, and the thoracic aorta was isolated for in vitro study of the endothelial integrity.. Allopurinol and febuxostat treatment induced significant reduction in body weight, systolic blood pressure, blood glucose, insulin, lipids, and improved kidney functions and endothelial integrity compared to nontreated rats. Febuxostat was more effective than allopurinol in normalizing serum fasting glucose, uric acid, catalase, and glutathione peroxidase activities.. Xanthine oxidase inhibitors ameliorated the effects of MS. Febuxostat was mildly superior to allopurinol in lowering serum fasting glucose, lipids, uric acid, and antioxidant enzyme activities.

Topics: Allopurinol; Animals; Blood Glucose; Blood Pressure; Body Weight; Catalase; Disease Models, Animal; Febuxostat; Glutathione Peroxidase; Insulin Resistance; Male; Metabolic Syndrome; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Considering the global health threat posed by kidney disease burden, a search for new nephroprotective drugs from our local flora could prove a powerful strategy to respond to this health threat. In this study we investigated the antihyperuricemic and nephroprotective potential of RA-3, a plant-derived lanosteryl triterpene. The antihyperuricemic and nephroprotective effect of RA-3 was investigated using the adenine and gentamicin induced hyperuricemic and nephrotoxicity rat model. Following the induction of hyperuricemia and nephrotoxicity, the experimental model rats (Sprague Dawley) were orally administered with RA-3 at 50 and 100 mg/kg body weight, respectively, daily for 14 days. Treatment of the experimental rats with RA-3, especially at 100 mg/kg, effectively lowered the serum renal dysfunction (blood urea nitrogen and creatinine) and hyperuricemic (uric acid and xanthine oxidase) biomarkers. These were accompanied by increased antioxidant status with decrease in malondialdehyde content. A much improved histomorphological structure of the kidney tissues was also observed in the triterpene treated groups when compared to the model control group. It is evident that RA-3 possesses the antihyperuricemic and nephroprotective properties, which could be vital for prevention and amelioration of kidney disease.

Topics: Animals; Biomarkers; Blood Urea Nitrogen; Body Weight; Creatinine; Hyperuricemia; Interleukin-6; Kidney; Lanosterol; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley; Triterpenes; Uric Acid; Xanthine Oxidase

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Chemokine CCL2; Collagen; Diabetic Nephropathies; Febuxostat; Glucose Intolerance; Hyperglycemia; Hyperuricemia; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mice, Obese; Oxidative Stress; Peptide Fragments; Uric Acid; Xanthine Oxidase

Febuxostat is an active xanthine oxidase (XO) inhibitor which is widely used in the treatment of hyperuricaemia. We aimed to evaluate the predictive performance of a pharmacokinetic-pharmacodynamic (PK-PD) model of the hypouricaemic effects of febuxostat.. Previously, we formulated a PK-PD model for predicting the hypouricaemic effects of febuxostat as a function of baseline serum urate levels, body weight, renal function and drug dose, using datasets reported in preapproval studies. Using an updated model with a sensitivity analysis, we examined the predictive performance of the PK-PD model, using datasets obtained from the medical records of patients who received febuxostat from March 2011 to December 2015 at Tokyo Women's Medical University Hospital. Multivariate regression analysis was performed to explore clinical variables to improve the predictive performance of the model.. A total of 1199 serum urate values were retrieved from 168 patients (age: 60.5 ± 17.7 years; 71.4% male) who were receiving febuxostat as a treatment for hyperuricaemia. There was a significant correlation (r = 0.68; P < 0.01) between the serum urate levels observed and those predicted by the modified PK-PD model. A multivariate regression analysis revealed that the predictive performance of the model could be improved further by considering comorbidities (such as diabetes mellitus), estimated glomerular filtration rate (eGFR) and the coadministration of loop diuretics (r = 0.77, P < 0.01).. The PK-PD model may be useful for predicting individualized maintenance doses of febuxostat in real-world patients.

Topics: Adult; Aged; Body Weight; Comorbidity; Datasets as Topic; Diabetes Mellitus; Dose-Response Relationship, Drug; Febuxostat; Female; Glomerular Filtration Rate; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Models, Biological; Sodium Potassium Chloride Symporter Inhibitors; Treatment Outcome; Uric Acid; Xanthine Oxidase

Conventionally, benzophenone-type molecules are beneficial for alleviating the UV exposure of humans. More importantly, various compounds with this skeleton have demonstrated various biological activities. In this paper, we report the anti-hyperuricemic effect of the benzophenone compound 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (HMS). Preliminarily, its molecular docking score and xanthine oxidase (XOD) inhibition suggested a good anti-hyperuricemic effect. Then, its anti-hyperuricemic effect, primary mechanisms and general toxicity were examined on a hyperuricemic mouse model which was established using potassium oxonate and hypoxanthine together. HMS demonstrated a remarkable anti- hyperuricemic effect which was near to that of the control drugs, showing promising perspective. General toxicity was assessed and it showed no negative effects on body weight growth and kidney function. Moreover, anti-inflammatory action was observed for HMS via spleen and thymus changes. Its anti-hyperuricemic mechanisms may be ascribed to its inhibition of XOD and its up-regulation of organic anion transporter 1 (OAT1) and down-regulation of glucose transporter 9 (GLUT9).

Topics: Animals; Benzophenones; Body Weight; Gene Expression Regulation; Glucose Transport Proteins, Facilitative; Humans; Hyperuricemia; Hypoxanthine; Kidney; Mice; Molecular Docking Simulation; Organic Anion Transport Protein 1; Oxonic Acid; Spleen; Thymus Gland; Xanthine Oxidase

We tested the hypothesis that estradiol (E2) protects against cardiorespiratory disorders and oxidative stress induced by chronic intermittent hypoxia (CIH) in adult female rats.. Sprague-Dawley female rats (230-250 g) were ovariectomized and implanted with osmotic pumps delivering vehicle or E2 (0.5 mg/kg/d). After 14 days of recovery, the rats were exposed to CIH (21%-10% O2: 8 h/d, 10 cycles per hour) or room air (RA). After 7 days of CIH or RA exposure, we measured arterial pressures (tail cuff), metabolic rate (indirect calorimetry), minute ventilation, the frequency of sighs and apneas at rest, and ventilatory responses to hypoxia and hypercapnia (whole body plethysmography). We collected the cerebral cortex, brainstem, and adrenal glands to measure the activity of NADPH and xanthine oxidase (pro-oxidant enzymes), glutathione peroxidase, and the mitochondrial and cytosolic superoxide dismutase (antioxidant enzymes) and measured lipid peroxidation and advanced oxidation protein products (markers of oxidative stress).. CIH increased arterial pressure, the frequency of apnea at rest, and the hypoxic and hypercapnic ventilatory responses and reduced metabolic rate. CIH also increased oxidant enzyme activities and decreased antioxidant activity in the cortex. E2 treatment reduced body weight and prevented the effects of CIH.. E2 prevents cardiorespiratory disorders and oxidative stress induced by CIH. These observations may help to better understand the underlying mechanisms linking menopause and occurrence of sleep apnea in women and highlight a potential advantage of hormone therapy.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Estradiol; Female; Glutathione Peroxidase; Heart; Hypercapnia; Hypoxia; NADP; Oxidative Stress; Rats; Rats, Sprague-Dawley; Respiration; Rest; Sleep Apnea Syndromes; Superoxide Dismutase; Xanthine Oxidase

This is the first report on the ability of soy sauce to effectively reduce the serum uric acid levels and xanthine oxidase (XOD) activities of hyperuricemic rats. Soy sauce was partitioned sequentially into ethyl acetate and water fractions. The ethyl acetate fraction with strong XOD inhibition effect was purified further. On the basis of xanthine oxidase inhibitory (XOI) activity-guided purification, nine compounds including 3,4-dihydroxy ethyl cinnamate, diisobutyl terephthalate, harman, daidzein, flazin, catechol, thymine, genistein, and uracil were obtained. It was the first time that 3,4-dihydroxy ethyl cinnamate and diisobutyl terephthalate had been identified from soy sauce. Flazin with hydroxymethyl furan ketone group at C-1 and carboxyl at C-3 exhibited the strongest XOI activity (IC50 = 0.51 ± 0.05 mM). According to fluorescence quenching and molecular docking experiments, flazin could enter into the catalytic center of XOD to interact with Lys1045, Gln1194, and Arg912 mainly by hydrophobic forces and hydrogen bonds. Flazin, catechol, and genistein not only were potent XOD inhibitors but also held certain antioxidant activities. According to ADME (absorption, distribution, metabolism, and excretion) simulation in silico, flazin had good oral bioavailability in vivo.

Topics: Animals; Body Weight; Carbolines; Drug Evaluation, Preclinical; Enzyme Inhibitors; Furans; Hyperuricemia; Male; Molecular Docking Simulation; Oxonic Acid; Rats, Sprague-Dawley; Soy Foods; Uric Acid; Xanthine Oxidase

Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

Topics: Acetophenones; Allopurinol; Analysis of Variance; Animals; Anti-Arrhythmia Agents; Antioxidants; Body Weight; Carbon Dioxide; Carotid Sinus; Catecholamines; Chemoreceptor Cells; Free Radical Scavengers; Heart Rate; Hypoxia; Losartan; Male; Oxidative Stress; Oxygen Consumption; Plethysmography; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Regression Analysis; Respiration; Tidal Volume; Time Factors; Tyrosine

To investigate the potential protective antioxidant role of ursodeoxycholic acid (UDCA), melatonin, and allopurinol treatment in cyclosporine (CsA)-induced hepatotoxicity.. Hepatotoxicity was established in Sprague-Dawley rats by daily administration of CsA. Treatment groups were additionally administered UDCA, melatonin, or allopurinol treatments. Rats that received no CsA and no treatments served as a control group. Liver samples from each group were examined by histopathologic analysis to determine the effects of CsA treatment on liver morphology. Biochemical assays were also used to determine the effect of CsA treatment on liver function, in the presence or absence of UDCA, melatonin, or allopurinol.. CsA treatment induced hepatotoxicity, resulting in sinusoidal dilatation, congestion, infiltration, hydropic degeneration, and loss of glycogen storage in the liver. From a molecular perspective, the CsA treatment increased levels of malondialdehyde (MDA) levels, decreased levels of reduced glutathione and xanthine oxidase, and decreased activities of superoxide dismutase and catalase. The CsA treatment also resulted in decreased serum total antioxidant capacity, whereas alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin levels, and total oxidant status were increased. Treatment with UDCA, melatonin, or allopurinol reduced the CsA-induced histopathologic changes, as compared with CsA-treated samples. In addition, UDCA, melatonin, or allopurinol treatment mitigated the CsA-induced effects on glutathione and MDA levels, and on superoxide dismutase and catalase activities, as well as reduced the CsA-mediated perturbations in serum levels of total antioxidant capacity, total oxidant status, and alkaline phosphatase.. UDCA, allopurinol, and melatonin may each help to protect against CsA-induced damage to liver tissues, possibly through effects on the antioxidant system.

Topics: Alanine Transaminase; Alkaline Phosphatase; Allopurinol; Animals; Antioxidants; Aspartate Aminotransferases; Bilirubin; Body Weight; Chemical and Drug Induced Liver Injury; Cyclosporine; Drug Evaluation, Preclinical; Liver; Male; Melatonin; Random Allocation; Rats, Sprague-Dawley; Ursodeoxycholic Acid; Xanthine Oxidase

The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo) on experimentally induced insulin resistance (IR) and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo), and allopurinol-treated control (Allo). IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion.

Topics: Aldehydes; Allopurinol; Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Diet, High-Fat; Enzyme Inhibitors; Fructose; Heart Rate; Insulin Resistance; Male; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Sodium Chloride, Dietary; Tumor Necrosis Factor-alpha

Endotoxin is a potent microbial mediator implicated in sepsis. We investigated the anti-inflammatory effect of leaf essential oil from Cinnamomum osmophloeum Kanehira (CO) of the linalool chemotype on endotoxin-injected mice. Mice were administered CO or vehicle by gavage before endotoxin injection and were killed 12 h after injection. Neither growth nor the organ weight or tissue weight to body weight ratio was affected by CO treatment. CO significantly lowered peripheral levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-18, interferon-γ, and nitric oxide and inhibited the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene (88), myeloid differentiation factor 2, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1, and Nod-like receptor family, pyrin domain containing 3 (NLRP3). CO also inhibited the activation of nuclear factor-ĸB, inhibited the activity of caspase-1 in small intestine, and ameliorated intestinal edema. Our data provide strong evidence for a protective effect of CO of the linalool chemotype in the endotoxin-induced systemic inflammatory response in close association with suppression of the TLR4 and NLRP3 signaling pathways in intestine.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Carrier Proteins; Cinnamomum; Cytokines; Disease Models, Animal; Endotoxins; Ileum; Inflammation Mediators; Intestinal Mucosa; Intestines; Lymph Nodes; Male; Mesentery; Mice; NF-kappa B; Nitrates; Nitrites; NLR Family, Pyrin Domain-Containing 3 Protein; Oils, Volatile; Organ Size; Plant Leaves; Protective Agents; Signal Transduction; Systemic Inflammatory Response Syndrome; Toll-Like Receptor 4; Xanthine Oxidase

The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats. Male albino Wistar rats were divided into four groups: control (normal saline 2.5mL/kg/dayi.p. on alternate days, a total of 6 doses); Doxorubicin (2.5mg/kg/dayi.p. on alternate days, a total of 6 doses), Doxorubicin+Febuxostat (10mg/kg/day oral) and Doxorubicin+Carvedilol (30mg/kg/day oral) for 14days. Febuxostat significantly ameliorated the doxorubicin-induced deranged cardiac functions as there was significant improvement in arterial pressures, left ventricular end diastolic pressure and inotropic and lusitropic states of the myocardium. These changes were well substantiated with biochemical findings, wherein febuxostat prevented the depletion of non-protein sulfhydryls level, with increased manganese superoxide dismutase level and reduced cardiac injury markers (creatine kinase-MB and B-type natriuretic peptide levels) and thiobarbituric acid reactive substances level. Febuxostat also exhibited significant anti-inflammatory (decreased expression of NF-κBp65, IKK-β and TNF-α) and anti-apoptotic effect (increased Bcl-2 expression and decreased Bax and caspase-3 expression and TUNEL positivity). Hematoxylin and Eosin, Masson Trichome, Picro Sirius Red and ultrastructural studies further corroborated with hemodynamic and biochemical findings showing that febuxostat mitigated doxorubicin-induced increases in inflammatory cells, edema, collagen deposition, interstitial fibrosis, perivascular fibrosis and mitochondrial damage and better preservation of myocardial architecture. In addition, all these changes were comparable to those produced by carvedilol. Thus, our results suggest that the antioxidant and anti-apoptotic effect of febuxostat contributes to its protective effects against doxorubicin-induced cardiotoxicity.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Biomarkers; Body Weight; Doxorubicin; Febuxostat; Heart; Male; Organ Size; Rats; Rats, Wistar; Superoxide Dismutase; Thiazoles; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

We evaluated the preventive effect of allopurinol on isoproterenol (ISO) induced myocardial infarction in aged rats. Twelve- to fourteen-month-old male Long Evans rats were divided into three groups: control, ISO, and ISO + allopurinol. At the end of the study, all rats were sacrificed for blood and organ sample collection to evaluate biochemical parameters and oxidative stress markers analyses. Histopathological examinations were also conducted to assess inflammatory cell infiltration and fibrosis in heart and kidneys. Our investigation revealed that the levels of oxidative stress markers were significantly increased while the level of cellular antioxidants, catalase activity, and glutathione concentration in ISO induced rats decreased. Treatment with allopurinol to ISO induced rats prevented the elevated activities of AST, ALT, and ALP enzymes, and the levels of lipid peroxidation products and increased reduced glutathione concentration. ISO induced rats also showed massive inflammatory cells infiltration and fibrosis in heart and kidneys. Furthermore, allopurinol treatment prevented the inflammatory cells infiltration and fibrosis in ISO induced rats. In conclusion, the results of our study suggest that allopurinol treatment is capable of protecting heart of ISO induced myocardial infarction in rats probably by preventing oxidative stress, inflammation, and fibrosis.

Topics: Alanine Transaminase; Alkaline Phosphatase; Allopurinol; Animals; Aspartate Aminotransferases; Body Weight; Catalase; Creatine Kinase, MB Form; Enzyme Inhibitors; Fibrosis; Glutathione; Heart; Isoproterenol; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Myocardium; Nitric Oxide; Oxidative Stress; Rats; Rats, Long-Evans; Xanthine Oxidase

To determine how many ambulatory older adults with chronic kidney disease receive medications that are contraindicated or dosed excessively given their level of renal function.. Cross-sectional retrospective study.. U.S. Department of Veterans Affairs (VA) clinics.. Individuals aged 65 and older with a creatinine clearance (CrCl) of 15 to 49 mL/min (N = 83,850; mean age 80; 96% male).. Forty medications that require dose adjustment or are contraindicated in people with impaired renal function were examined. Medication use and CrCl (calculated using the Cockroft-Gault equation) were assessed using VA pharmacy, laboratory, and other data sources as of October 2007.. Thirteen percent of older veterans with a CrCl of 30 to 49 mL/min and 32% of those with a CrCl of 15 to 29 mL/min received one or more drugs that were contraindicated or prescribed at an excessive dose given the individual's level of renal function. The strongest risk factor for renally inappropriate prescribing was number of medications used; the risk of receiving renally inappropriate medications was 5.5 times as high (95% confidence interval = 5.1-5.9) in older adults taking 10 or more medications as in those taking one to three medications. Ranitidine, allopurinol, and metformin together accounted for 76% of renally misprescribed medications in individuals with a CrCl of 30 to 49 mL/min. Glyburide, ranitidine, gemfibrozil, carvedilol, and allopurinol accounted for 47% of renally misprescribed drugs for individuals with a CrCl of 15 to 29 mL/min.. Inappropriate prescribing of renally cleared medications is common in ambulatory older veterans, with only a few medications accounting for most of these prescribing problems.

Topics: Aged; Aged, 80 and over; Allopurinol; Aminohydrolases; Body Weight; Comorbidity; Cross-Sectional Studies; Female; Humans; Inappropriate Prescribing; Male; Metformin; Ranitidine; Renal Insufficiency, Chronic; Retrospective Studies; United States; Veterans

Microwave (MW) radiation produced by wireless telecommunications and a number of electrical devices used in household or in healthcare institutions may adversely affects the reproductive pattern. Present study aimed to investigate the protective effects of melatonin (is well known antioxidant that protects DNA, lipids and proteins from free radical damage) against oxidative stress-mediated testicular impairment due to long-term exposure of MWs. For this, 70-day-old male Wistar rats were divided into four groups (n = 6/group): Sham exposed, Melatonin (Mel) treated (2 mg/kg), 2.45 GHz MWs exposed and MWs + Mel treated. Exposure took place in Plexiglas cages for 2 h a day for 45 days where, power density (0.21 mW/cm(2)) and specific absorption rate (SAR 0.14 W/Kg) were estimated. After the completion of exposure period, rats were sacrificed and various stress related parameters, that is LDH-X (lactate dehydrogenase isoenzyme) activity, xanthine oxidase (XO), ROS (reactive oxygen species), protein carbonyl content, DNA damage and MDA (malondialdehyde) were performed. Result shows that melatonin prevent oxidative damage biochemically by significant increase (p < 0.001) in the levels of testicular LDH-X, decreased (p < 0.001) levels of MDA and ROS in testis (p < 0.01). Meanwhile, it reversed the effects of MWs on XO, protein carbonyl content, sperm count, testosterone level and DNA fragmentation in testicular cells. These results concluded that the melatonin has strong antioxidative potential against MW induced oxidative stress mediated DNA damage in testicular cells.

Topics: Animals; Apoptosis; Body Weight; DNA Damage; Fertility; L-Lactate Dehydrogenase; Male; Malondialdehyde; Melatonin; Microwaves; Oxidative Stress; Protein Carbonylation; Radiation-Protective Agents; Rats; Rats, Wistar; Testis; Testosterone; Xanthine Oxidase

Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE(-/-) mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(-/-) mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Weight; Cholesterol; Cytokines; Disease Models, Animal; Endothelial Cells; Febuxostat; Gout Suppressants; Inflammation; L-Lactate Dehydrogenase; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Plaque, Atherosclerotic; Reactive Oxygen Species; Thiazoles; Xanthine Oxidase

Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation.. Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity.. Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers.. Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Allopurinol; Anaerobiosis; Animals; Blood Glucose; Body Weight; Buffers; Cell Respiration; Cold Ischemia; Electron Transport; Fasting; Fatty Liver; Glucose Intolerance; Glutathione; Hydrogen-Ion Concentration; Insulin; Insulin Resistance; Liver; Male; Mice, Inbred C57BL; Mice, Obese; Mitochondria, Liver; Organ Preservation Solutions; Oxidative Phosphorylation; Raffinose; Thinness

Social isolation is common in the elderly exerting negative effects on neuroimmunoendocrine communication. Nevertheless physiological responses to a stressful situation may vary according to diverse factors. This work studies the differences in the immune response of aged male rats socially isolated depending on the anxiety levels produced. Social isolation impaired certain immunological parameters, but a more anxious response to isolation was associated to global severe immunosuppression and greater oxidative state. Thus, responding anxiously to isolation may suppose a more potent risk of morbidity and mortality further than isolation and anxiety by themselves, particularly in elderly subjects.

Topics: Animals; Anxiety; Body Weight; Cell Proliferation; Chemotaxis; Cytokines; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Immune System Diseases; Killer Cells, Natural; Leukocytes; Male; Maze Learning; Oxidative Stress; Rats; Rats, Wistar; Social Isolation; Xanthine Oxidase

A series of studies have recently demonstrated that the oxidative stress, nuclear factor-kappa B (NF-κB) activation and the subsequent coordinated inflammatory responses played an important role in the pathogenesis of urate nephropathy (UN). Polydatin has been suggested to have the properties of anti-oxidative, anti-inflammatory and nephroprotective effects. However, the possible protective and beneficial effects of polydatin on UN are not fully elucidated. Therefore, we investigated the potential beneficial effects and possible mechanisms of polydatin on UN. In this study, polydatin showed inhibitory activities on xanthine oxidase to repress the level of serum uric acid in vivo and in vitro. Further investigations revealed that polydatin displayed little toxic effects and significantly ameliorated the renal function in fructose-induced UN mice. The nephroprotective activities of polydatin was not only due to the effects on remarkably attenuating the oxidative stress induced by uric acid, but also on markedly suppressing the oxidative stress-related inflammatory cascade, including decreasing the expressions of NF-κB p65, COX-2 and iNOS proteins and inhibiting the productions of TNF-α, PGE(2) and IL-1β. These findings elucidated that polydatin exhibited prominent nephroprotective activities and low toxic effects.

Topics: Animals; Blood Chemical Analysis; Body Weight; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Drugs, Chinese Herbal; Fructose; Glucosides; Inflammation; Interleukin-1beta; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred Strains; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Stilbenes; Tumor Necrosis Factor-alpha; Uric Acid; Xanthine Oxidase

Preventive effects of ellagic acid against doxorubicin-induced cardiac oxidative, inflammatory and apoptotic stress were examined. This agent at 0.25, 0.5 or 1% was added in feed and supplied to mice for 8 weeks, and followed by doxorubicin treatment. Ellagic acid intake increased its deposit in heart. Pre-intake of this compound at 0.5 and 1% significantly attenuated doxorubicin caused increase in plasma creatine phosphokinase activity. Doxorubicin treatment decreased glutathione content, increased reactive oxygen species (ROS), malonyldialdehyde (MDA), interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels, declined glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities, and enhanced xanthine oxidases (XO) activity in heart. Ellagic acid intake dose-dependently reserved glutathione content, lowered ROS and MDA levels, and reduced XO activity. This compound at 0.5 and 1% retained GPX and SOD activities, and decreased cytokines in heart. Doxorubicin treatment raised cardiac activity and protein production of caspase-3, nuclear factor kappa B (NF-κB) p50 and p65. Ellagic acid dose-dependently lowered caspase-3 activity and cleaved caspase-3 formation, and at 0.5 and 1% declined activity and protein level of NF-κB. Doxorubicin treatment also up-regulated cardiac expression of p-p38, p-ERK 1/2 and p-JNK, and ellagic acid at 0.5 and 1% suppressed p-p38 expression and at 1% down-regulated p-ERK 1/2 expression. These findings suggest that ellagic acid is a potent cardiac protective agent against doxorubicin.

Topics: Animals; Antibiotics, Antineoplastic; Biomarkers; Blotting, Western; Body Weight; Cardiotonic Agents; Caspase 3; Chromatography, High Pressure Liquid; Creatine Kinase; Doxorubicin; Eating; Ellagic Acid; Glutathione; Heart Diseases; Inflammation Mediators; L-Lactate Dehydrogenase; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Myocardium; NF-kappa B; Xanthine Oxidase

This work investigates the effects of oxidative stress due to exhaustive training on uncoupling protein 2 (UCP2) and Bcl-2/Bax in rat skeletal muscles. A total of 18 Sprague-Dawley female rats were randomly divided into three groups: the control group (CON), the trained control group (TC), and the exhaustive trained group (ET). Malondialdehyde (MDA), superoxide dismutase (SOD), xanthine oxidase (XOD), ATPase, UCP2, and Bcl-2/Bax ratio in red gastrocnemius muscles were measured. Exhaustive training induced ROS increase in red gastrocnemius muscles, which led to a decrease in the cell antiapoptotic ability (Bcl-2/Bax ratio). An increase in UCP2 expression can reduce ROS production and affect mitochondrial energy production. Thus, oxidative stress plays a significant role in overtraining.

Topics: Adenosine Triphosphatases; Animals; bcl-2-Associated X Protein; Body Weight; Female; Ion Channels; Malondialdehyde; Mitochondrial Proteins; Muscle, Skeletal; Oxidative Stress; Physical Conditioning, Animal; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Uncoupling Protein 2; Xanthine Oxidase

Cachexia is a common co-morbidity in cancer occurring in up to 80% of patients depending on the type of cancer. Uric acid (UA), the end-product of the purine metabolism, is elevated in cachexia due to tissue wasting and upregulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO-dependent production of oxygen free radicals (reactive oxygen species; ROS) and correlate with metabolic illness and poor survival. We hypothesized that XO-inhibition might reduce inflammatory signals accounting for tissue wasting and improve survival in experimental cancer cachexia. Animals were inoculated intraperitoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol [Allo, low (LD) and high dose (HD) 4 and 40 mg/kg/d] and its more effective active metabolite oxypurinol (Oxy, 4 and 40 mg/kg/d) or placebo for 15 days. Weight loss and tissue wasting of both fat and lean tissue (assessed by NMR-scanning) was reduced by both LD and HD Allo and LD-Oxy, but not by HD-Oxy. A robust induction of XO-activity for generation of reactive oxygen species was seen in the placebo group (assessed by electron paramagnetic spectroscopy), which was reduced by XO-inhibition. Increased ROS induced cytokine signaling, proteolytic activity and tissue degradation were all attenuated by XO inhibition. Survival was significantly and dose dependently improved. Food intake and spontaneous locomotor activity were higher, indicating a higher quality of life. Inhibition of XO can reduce tissue wasting and improve survival in cancer cachexia and clearly clinical studies are needed.

Topics: Allopurinol; Animals; Body Composition; Body Weight; Cachexia; Caspase 3; Enzyme Inhibitors; Male; Neoplasms; Oxidative Stress; Oxypurinol; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Treatment Outcome; Uric Acid; Xanthine Oxidase

Recently, sodium tungstate was suggested to improve cardiac performance of diabetic rats in perfused hearts based on its insulinomimetic activity. In this study, we aimed to investigate the cellular and molecular mechanisms underlying this beneficial effect of sodium tungstate. Tungstate was administered (100 mg/kg/day) to diabetic and control rats intragastrically for 6 weeks. Blood glucose levels increased, whereas body weight, heart weight and plasma insulin levels decreased significantly in diabetic animals. Interestingly, none of these parameters was changed by tungstate treatment. On the other hand, fractional shortening and accompanying intracellular Ca(2+) [Ca(2+)](i) transients of isolated ventricular myocytes were measured, and sodium tungstate was found to improve the peak shortening and the amplitude of [Ca(2+)](i) transients in diabetic cardiomyocytes. Potassium and L-type Ca(2+) currents were also recorded in isolated ventricular cells. Significant restoration of suppressed I (to) and I (ss) was achieved by tungstate administration. Nevertheless, L-type calcium currents did not change either in untreated or treated diabetic rats. Tissue biochemical parameters including TBARS, protein carbonyl content, xanthine oxidase (XO) and xanthine dehydogenase (XDH) were also determined, and diabetes revealed a marked increase in TBARS and carbonyl content which were decreased significantly by tungstate treatment. Conversely, although XO and XDH activities didn't change in untreated diabetic rats, a remarkable but insignificant decrease was detected in treated animals. In conclusion, tungstate treatment improved diabetes-induced contractile abnormalities via restoration of dysregulated [Ca(2+)](i) and altered ionic currents. This beneficial effect is due to antioxidant property of sodium tungstate rather than normalization of hyperglycemia.

Topics: Animals; Blood Glucose; Body Weight; Calcium; Calcium Channels, L-Type; Cardiotonic Agents; Diabetes Complications; Diabetes Mellitus, Experimental; Electrophysiological Phenomena; Heart; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Myocardial Contraction; Myocytes, Cardiac; Organ Size; Oxidative Stress; Patch-Clamp Techniques; Protein Carbonylation; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Tungsten Compounds; Xanthine Dehydrogenase; Xanthine Oxidase

Hyperuricemia, hyperlipidemia and inflammation are associated with diabetic nephropathy. The NLRP3 inflammasome-mediated inflammation is recently recognized in the development of kidney injury. Urate and lipid are considered as danger signals in the NLRP3 inflammasome activation. Although dietary flavonoid quercetin and allopurinol alleviate hyperuricemia, dyslipidmia and inflammation, their nephroprotective effects are currently unknown. In this study, we used streptozotocin (STZ)-induced diabetic nephropathy model with hyperuricemia and dyslipidemia in rats, and found over-expression of renal inflammasome components NLRP3, apoptosis-associated speck-like protein and Caspase-1, resulting in elevation of IL-1β and IL-18, with subsequently deteriorated renal injury. These findings demonstrated the possible association between renal NLRP3 inflammasome activation and lipid accumulation to superimpose causes of nephrotoxicity in STZ-treated rats. The treatment of quercetin and allopurinol regulated renal urate transport-related proteins to reduce hyperuricemia, and lipid metabolism-related genes to alleviate kidney lipid accumulation in STZ-treated rats. Furthermore, quercetin and allopurinol were found to suppress renal NLRP3 inflammasome activation, at least partly, via their anti-hyperuricemic and anti-dyslipidemic effects, resulting in the amelioration of STZ-induced the superimposed nephrotoxicity in rats. These results may provide a basis for the prevention of diabetes-associated nephrotoxicity with urate-lowering agents such as quercetin and allopurinol.

Topics: Acute Kidney Injury; Allopurinol; Analysis of Variance; Animals; Blood Urea Nitrogen; Blotting, Western; Body Weight; Carrier Proteins; Creatinine; Diabetic Nephropathies; DNA Primers; Gene Expression Regulation; Inflammasomes; Lipid Metabolism; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Organ Size; Quercetin; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear; Streptozocin; Uric Acid

Total or partial pancreatectomy followed by autologous islet transplantation is a therapeutic option for the treatment of refractory chronic pancreatitis (CP). Maximization of islet yields from fibrotic and inflamed organs is crucial for prevention of posttransplant diabetes. We adapted technical advancements developed for islet allotransplantation toward islet autotransplantation. Eight patients (two men, six women; ages 24-58 years) underwent total (n = 7) or partial (n = 1) pancreatectomy for the treatment of CP refractory to maximal medical management. Pancreata were preserved in UW solution (UW group) in initial three cases and the last five pancreata were preserved with pancreatic ductal injection followed by ET-Kyoto/oxygenated PFC solutions (DI+TLM group). Islets were isolated by modified Ricordi method and were purified only in one case. All islet infusions were performed under general anesthesia via direct vein injection into the portal venous system with pressure monitoring. Total islet yields (129,314 ± 51,627 vs. 572,841 ± 116,934 IEQ, p < 0.04), islet yield/pancreas weight (1,233 ± 359 vs. 6,848 ± 847 IEQ/g, p < 0.003), and islet yield/patient body weight (1,951 ± 762 vs. 7,305 ± 1,531 IEQ/kg, p < 0.05) were significantly higher in the DI+TLM group when compared to the UW group. Pellet size was also higher (5.3 ± 0.3 vs. 13.5 ± 3.4 ml) in the DI+TLM group, suggesting that this method of preservation effectively protected pancreatic tissue against autolysis. First month posttransplant basal C-peptide and the secretory unit of islet transplant objects (SUITO) index were also higher in the DI+TLM group when compared to the UW group (2.0 ± 0.3 vs. 1.4 ± 0.4 ng/ml and 42.6 ± 12.7 vs. 14.6 ± 5.6, respectively). There were no technical complications related to the infusion. Our results suggest that higher islet yields can be achieved even from chronically inflamed and fibrotic organs using DI+TLM. The techniques applied for islet isolations from normal pancreata are showing promise for fibrotic pancreata from CP patients.

Topics: Adenosine; Adult; Allopurinol; Body Weight; C-Peptide; Epoprostenol; Female; Fluorocarbons; Follow-Up Studies; Glutamine; Glutathione; Humans; Hydroxyethyl Starch Derivatives; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Magnesium Sulfate; Male; Middle Aged; Niacinamide; Organ Preservation; Organ Preservation Solutions; Pancreatitis, Chronic; Raffinose; Transplantation, Autologous; Trehalose

Fructus Psoraleae (FP) has been widely used to heal skin diseases as well as osteoporosis, osteomalacia, and bone fracture. There also exist many clinical reports about FP-induced hepatotoxicity associated with acute cholestatic hepatic injury. However, the FP-induced hepatotoxicity and the underlying mechanisms remain unclear.. The present study aims to determine the hepatotoxicity of FP in Sprague-Dawley (SD) rats and to investigate the underlying mechanisms.. Sprague-Dawley rats of both sexes were intragastrically administered with the EtOH extract of FP (EEFP) at doses of 1.875, 1.25 and 0.625 g/kg for 28 day. Body weight, relative liver weight, biochemical analysis, histopathology, the mRNA and protein expression of Cholesterol 7α-hydroxylase (CYP7A1), farnesoid X receptor (FXR), bile-salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), multidrug resistance-associated protein 3 (MRP3) were evaluated to study the EEFP-induced hepatotoxicity and its underlying mechanisms.. Many abnormalities were observed in the EEFP-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, increased weight of liver, and decreased concentration of bile acid in bile. The mRNA and protein expression of CYP7A1, MRP3, MRP2, BSEP increased and the expression of FXR decreased in EEFP-treated female groups; the mRNA and protein of FXR and CYP7A1 decreased and that of the others remained the same in EEFP-treated male groups.. In conclusion, we provide evidence for the first time that EEFP can induce sex-related cholestatic hepatotoxicity, and that female rats are more sensitive to EEFP-induced hepatotoxicity, which involves the destruction of the biosynthesis and transportation of bile acid. Further investigation is still needed to uncover the mechanism of the sex-dimorphic EEFP-induced hepatotoxicity.

Topics: Animals; Bile; Body Weight; Chemical and Drug Induced Liver Injury; Cholestasis; Ethanol; Female; Gene Expression Regulation; Liver; Male; Organ Size; Plant Extracts; Psoralea; Rats; Rats, Sprague-Dawley; Seeds; Sex Factors; Solvents; Xanthine Oxidase

It is well established that oxidative and conjugative enzyme activity differs between obese and healthy-weight adults. However, the effect of obesity on drug metabolism in children has not been studied extensively. This study examined whether obese and healthy-weight children vary with respect to oxidative enzyme activity of CYP1A2, xanthine oxidase (XO) and conjugative enzyme activity of N-acetyltransferase 2 (NAT2).. In vivo CYP1A2, XO and NAT2 activity was assessed in obese (n= 9) and lean (n= 16) children between the ages of 6-10 years using caffeine (118.3 ml Coca Cola®) as probe. Urine samples were collected in 2-h increments over 8 h. Caffeine and metabolites were measured using LC/MS, and urinary metabolic ratios were determined based on reported methods.. Sixteen healthy-weight and nine obese children were evaluated. XO activity was elevated in paediatric obese volunteers compared with non-obese paediatric volunteers (XO metabolic ratio of 0.7 ± 0.06 vs. 0.6 ± 0.06, respectively, 95% CI 0.046, 0.154, P < 0.001). NAT2 activity was fivefold higher in the obese (1 ± 0.4) as compared with non-obese children (0.2 ± 0.1), 95% CI 0.26, 1.34, P < 0.05. However, no difference was observed in CYP1A2 activity between the groups (95% CI -2.72, 0.12, P > 0.05).. This study provides evidence that obese children have elevated XO and NAT2 enzyme activity when compared with healthy-weight controls. Further studies are needed to determine how this may impact the efficacy of therapeutic agents that may undergo metabolism by these enzymes.

Topics: Arylamine N-Acetyltransferase; Biomarkers; Body Weight; Caffeine; Case-Control Studies; Child; Cytochrome P-450 CYP1A2; Female; Humans; Male; Models, Statistical; Obesity; Xanthine Oxidase

The purpose of this study was to determine the effects of allopurinol (AL) on xanthine oxidoreductase (XOR) activity and uric acid (UA) levels in chickens. Thirty 5-week-old broilers were divided into three groups and fed 0 (control), 25 (AL25) or 50 (AL50) mg AL per kg of body mass for 5 weeks. Chicks were weighed twice weekly and leukocyte oxidative activity (LOA) and plasma purine levels were determined weekly in five birds per group. Chicks were sacrificed after 2 or 5 weeks, and samples from tissues were taken for analysis of XOR activity. Plasma UA concentrations were lower (P<0.001) and xanthine and hypoxanthine concentrations were greater (P<0.001) in AL25 and AL50 birds compared to controls, whereas no differences (P=0.904) were detected in allantoin concentrations. By week 5, body mass was reduced (P<0.001) to 84.0 and 65.1% of that in controls for AL25 and AL50 broilers, respectively, and LOA was 4.1 times greater (P<0.05) in AL25 compared to control birds. Liver XOR activity was increased by 1.1 and 1.2 times in AL25 and AL50 birds, but there was no change (P>0.05) in XOR activity in the pancreas and intestine. These results suggest that AL effect on XOR activity is tissue dependent.

Topics: Age Factors; Allantoin; Allopurinol; Animals; Blood Glucose; Body Weight; Chickens; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Hypoxanthine; Intestines; Liver; Male; Oxidative Stress; Pancreas; Uric Acid; Xanthine; Xanthine Dehydrogenase; Xanthine Oxidase

This study tested the hypothesis that resveratrol supplementation would lower oxidative stress in exercised muscles of aged mice. Young (3 months) and aged (27 months) C57BL/6 mice received a control or a 0.05% trans-resveratrol-supplemented diet for 10 days. After 7 days of dietary intervention, 20 maximal electrically evoked isometric contractions were obtained from the plantar flexors of one limb in anesthetized mice. Exercise was conducted for three consecutive days. Resveratrol supplementation blunted the exercise-induced increase in xanthine oxidase activity in muscles from young (25%) and aged (53%) mice. Resveratrol lowered H(2)O(2) levels in control (13%) and exercised (38%) muscles from aged animals, reduced Nox4 protein in both control and exercised muscles of young (30%) and aged mice (40%), and increased the ratio of reduced glutathione to oxidized glutathione in exercised muscles from young (38%) and aged (135%) mice. Resveratrol prevented the increase in lipid oxidation, increased catalase activity, and increased MnSOD activity in exercised muscles from aged mice. These data show that dietary resveratrol suppresses muscle indicators of oxidative stress in response to isometric contractions in aged mice.

Topics: Aging; Animals; Body Weight; Citrate (si)-Synthase; Eating; Glutathione; Hydrogen Peroxide; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle Fatigue; Muscle, Skeletal; NADPH Oxidases; Oxidative Stress; Resveratrol; Stilbenes; Superoxide Dismutase; Xanthine Oxidase

Obesity is frequently associated with endothelial dysfunction. We hypothesized that high-fat feeding dysregulates the balance between endothelial derived nitric oxide and superoxide formation. Furthermore, we examined whether caloric restriction could reverse the detrimental vascular effects related to obesity. Male C57Bl/6 mice were fed with normal-fat diet (fat 17%) or high-fat diet (fat 60%) for 150 days. After establishment of obesity at day 100, a subgroup of obese mice were put on caloric restriction (CR) (70% of ad libitum energy intake) for an additional 50 days. At day 100, aortic rings from obese mice receiving high-fat diet showed impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Caloric restriction reversed high-fat diet-induced endothelial dysfunction. At day 150, impaired vasodilatory responses to ACh in obese mice without caloric restriction were markedly improved by preincubation with the tetrahydrobiopterin (BH(4)) precursor sepiapterin and L-arginine, a substrate for endothelial nitric oxide synthase (eNOS). Additionally, inhibition of vascular arginase by L-norvaline partially, and superoxide scavenging by Tiron completely, restored endothelial cell function. Obese mice showed increased vascular superoxide production, which was diminished by endothelial denudation, pretreated of the vascular rings with apocynin (an inhibitor of reduced nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), oxypurinol (an inhibitor of xanthine oxidase), N(G)-nitro-L-arginine methyl ester (LNAME; an inhibitor of eNOS), or by adding the BH(4) precursor sepiapterin. Caloric restriction markedly attenuated vascular superoxide production. In obese mice on CR, endothelial denudation increased superoxide formation whereas vascular superoxide production was unaffected by L-NAME. Western blot analysis revealed decreased phosphorylated eNOS (Ser1177)-to-total eNOS expression ratio in obese mice as compared to lean controls, whereas the phospho-eNOS/NOS ratio in obese mice on CR did not differ from the lean controls. In conclusion, the present study suggests that caloric restriction reverses obesity induced endothelial dysfunction and vascular oxidative stress, and underscores the importance of uncoupled eNOS in the pathogenesis.

Topics: Animals; Arginase; Biopterins; Body Weight; Caloric Restriction; Cardiovascular Diseases; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Free Radical Scavengers; Male; Mice; Mice, Inbred C57BL; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Phosphorylation; Superoxides; Time Factors; Vasodilation; Vasodilator Agents; Xanthine Oxidase

Both ACE inhibitors and allopurinol have been shown to partially prevent metabolic syndrome induced by fructose. We tested the hypothesis that combined therapy might be more effective at blocking the metabolic syndrome induced with fructose.. Male Sprague-Dawley rats were fed a high fructose diet with or without allopurinol, captopril, or the combination for 20 weeks. A control group received a normal diet. All groups were pair-fed to assure equivalent caloric intake.. Despite reduced energy intake, the fructose-fed rats developed features of metabolic syndrome including elevated blood pressure, abdominal obesity, hypertriglyceridemia, hyperuricemia and hyperinsulinemia. While both allopurinol and captopril alone tended to reduce features of the metabolic syndrome, the combined therapy was synergistic, with significant reduction in blood pressure, less accumulation of abdominal fat, an improvement in the dyslipidemia and a complete prevention of insulin resistance.. A high fructose diet can induce metabolic syndrome even in the setting of caloric restriction. Captopril and allopurinol synergistically reduce features of the metabolic syndrome, especially hypertension, insulin resistance and dyslipidemia. Combination allopurinol and ACE inhibitor therapy might provide a superior means to prevent diabetes and cardiovascular disease.

Topics: Allopurinol; Angiotensin-Converting Enzyme Inhibitors; Animal Feed; Animals; Antimetabolites; Body Weight; Captopril; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Energy Metabolism; Fructose; Insulin Resistance; Male; Metabolic Syndrome; Rats; Rats, Sprague-Dawley

Xanthine oxidase (XO) expression is increased in the failing heart, and animal studies in rodents and dogs showed that XO inhibition with allopurinol can improve left ventricular (LV) function and myocardial oxygen efficiency in the failing heart. The purpose of this study was to determine whether chronic XO inhibition by allopurinol or febuxostat, an investigational, potent non-purine, selective inhibitor of XO, could prevent or treat the progression of congestive heart failure (CHF) induced by coronary artery ligation in rabbits, a species that exhibits low intrinsic XO activity similar to humans. One day after coronary ligation, rabbits were assigned to one of four groups (n = 7-8/group): control group (vehicle for 49 days), early treatment (prevention) group (febuxostat for 49 days), and two delayed-treatment groups (vehicle for 21 days followed by either febuxostat or allopurinol for 28 days). An echocardiogram of the LV was obtained on Days 0 (prior to surgery), 21, and 49. Control rabbits developed CHF by Day 21 (significant reduction in LV shortening fraction and ejection fraction, thinning of the LV posterior wall, and increases in LV internal dimensions and end-diastolic volume). Early preventive treatment with febuxostat significantly lessened the reduction of LV function when compared to vehicle on both Days 21 and 49. These cardiac functional improvements were accompanied by moderately less severe changes in LV dimensional parameters relative to vehicle controls. In contrast, when treatments with XO inhibitors were started after the establishment of CHF, no significant relative improvements in cardiac functional or dimensional parameters were observed. These results suggest that chronic preventive treatment with an XO inhibitor initiated shortly after myocardial infarction can delay or prevent the onset of CHF, and that XO inhibition initiated after establishment of the disease does not offer cardiac protection. In contrast to previous rodent studies which do suggest a cardiovascular (CV) benefit of delayed XO inhibition, the results of this rabbit study are in keeping with those of recently completed studies in severe CHF patients treated with oxypurinol, the active metabolite of allopurinol, in which no clinical benefit was observed. This may be due to the fact that rodents have relatively high levels of XO activity, while the levels in rabbits and humans are intrinsically low, suggesting that the rabbit may be the preferred model for inves

Topics: Allopurinol; Animals; Body Weight; Echocardiography; Enzyme Inhibitors; Febuxostat; Heart Failure; Male; Myocardial Infarction; Myocardium; Organ Size; Rabbits; Thiazoles; Time Factors; Xanthine Oxidase

Increased fructose consumption is associated with hyperuricemia, metabolic syndrome, and renal damage. This study evaluated whether febuxostat (Fx), an investigational nonpurine, and selective xanthine oxidase inhibitor, could alleviate the features of metabolic syndrome as well as the renal hemodynamic alterations and afferent arteriolopathy induced by a high-fructose diet in rats. Two groups of rats were fed a high-fructose diet (60% fructose) for 8 wk, and two groups received a normal diet. For each diet, one group was treated with Fx (5-6 mg.kg(-1).day(-1) in the drinking water) during the last 4 wk (i.e., after the onset of metabolic syndrome), and the other received no treatment (placebo; P). Body weight was measured daily. Systolic blood pressure and fasting plasma uric acid (UA), insulin, and triglycerides were measured at baseline and at 4 and 8 wk. Renal hemodynamics and histomorphology were evaluated at the end of the study. A high-fructose diet was associated with hyperuricemia, hypertension, as well as increased plasma triglycerides and insulin. Compared with fructose+P, fructose+Fx rats showed significantly lowered blood pressure, UA, triglycerides, and insulin (P < 0.05 for all comparisons). Moreover, fructose+Fx rats had significantly reduced glomerular pressure, renal vasoconstriction, and afferent arteriolar area relative to fructose+P rats. Fx treatment in rats on a normal diet had no significant effects. In conclusion, normalization of plasma UA with Fx in rats with metabolic syndrome alleviated both metabolic and glomerular hemodynamic and morphological alterations. These results provide further evidence for a pathogenic role of hyperuricemia in fructose-mediated metabolic syndrome.

Topics: Animals; Blood Pressure; Body Weight; Energy Intake; Febuxostat; Fructose; Gout Suppressants; Kidney; Male; Metabolic Syndrome; Rats; Rats, Sprague-Dawley; Renal Circulation; Thiazoles; Xanthine Oxidase

A two-phase cross-over therapeutic study was performed with 19 green iguanas (Iguana iguana) maintained within a preferred optimum temperature range of 26 to 37 degrees C. During phase 1, they were fed a normal vegetarian diet and medicated orally with either allopurinol or a placebo control once a day for seven days. Uric acid concentrations, total protein, packed-cell volumes (pcv) and bodyweights were recorded from each lizard before and after treatment to determine the effects of allopurinol. In phase 2, after a 10-day washout period, the iguanas were fed a high protein diet to induce hyperuricaemia. Normo- and hyperuricaemic iguanas that received 24.2 (3.2) mg/kg allopurinol had significantly lower mean (sd) uric acid concentrations (100.3 [53.1] micromol/l) than the controls (159.3 [100.3] micromol/l). There were no detectable interactions between the doses of allopurinol or placebo, and the iguanas' diet, weight, pcv or total protein. The allopurinol was well tolerated, and there was no significant clinical, gross or histological evidence of hepatic or renal toxicity in the iguanas that received the drug. However, in the kidneys of the hyperuricaemic iguanas that did not receive allopurinol there were proliferative changes in the glomeruli and degeneration of tubular epithelia. Allopurinol given orally at 25 mg/kg daily is able to reduce plasma uric acid levels by 41 to 45 per cent, and is therefore recommended for the treatment of hyperuricaemia in the green iguana.

Topics: Administration, Oral; Allopurinol; Animals; Antimetabolites; Blood Proteins; Body Weight; Cross-Over Studies; Diet; Dietary Proteins; Hematocrit; Hyperuricemia; Iguanas; Kidney; Liver; Male; Random Allocation; Uric Acid

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome. Thiazide diuretics are frequently used in these patients for treatment of hypertension, but they also exacerbate metabolic syndrome. Rats on high-fructose diets that are given thiazides exhibit potassium depletion and hyperuricemia. Potassium supplementation improves their insulin resistance and hypertension, whereas allopurinol reduces serum levels of uric acid and ameliorates hypertension, hypertriglyceridemia, hyperglycemia, and insulin resistance. Both potassium supplementation and treatment with allopurinol also increase urinary nitric oxide excretion. We suggest that potassium depletion and hyperuricemia in rats exacerbates endothelial dysfunction and lowers the bioavailability of nitric oxide, which blocks insulin activity and causes insulin resistance during thiazide usage. Addition of potassium supplements and allopurinol with thiazides might be helpful in the management of metabolic syndrome.

Topics: Allopurinol; Animals; Blood Pressure; Body Weight; Diuretics; Fructose; Gout Suppressants; Hydrochlorothiazide; Hyperglycemia; Hypertension; Hypertriglyceridemia; Hyperuricemia; Hypokalemia; Insulin; Insulin Resistance; Kidney; Male; Metabolic Syndrome; Nitric Oxide; Potassium; Rats; Rats, Sprague-Dawley; Sodium; Uric Acid

Cadmium (Cd) exposure has been recognized to result in a wide variety of cellular responses, including oxidative stress and body weight loss. The aim of the present study was to examine the effect of lycopene supplementation on the antioxidant defense system, lipid peroxidation (LPO) level, nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) production, and body weight in Cd-exposed rats. Animals were divided into four groups (n = 7): control, Cd-treated, Cd plus lycopene-treated, and lycopene-treated. Cadmium (as CdCl2) was administrated orally for 20 days (6.6 mg kg(-1) day(-1)), and lycopene (10 mg kg(-1) day(-1)) was similarly administered. Lycopene administration significantly suppressed Cd-induced LPO in plasma and kidney homogenates. Lycopene also reversed Cd-decreased body weight compared to the control. Cadmium treatment had diverse effects on the antioxidant enzyme activities. Although antioxidant superoxide dismutase activity was unchanged, glutathione peroxidase activity was decreased, and catalase activity was elevated in kidney homogenates of Cd-administrated group. However, lycopene treatment reversed Cd-changed enzyme activities to the control level. Xanthine oxidase activity and TNF-alpha concentration were not altered by Cd administration, indicating that superoxide anion production and inflammation were not stimulated. Cadmium did not change NO levels in kidney homogenates but decreased those in plasma, and this effect was not prevented by lycopene supplementation. The result suggests that consumption of adequate levels of lycopene may be useful to prevent heavy-metal-induced LPO and body weight loss.

Topics: Administration, Oral; Animals; Antioxidants; Body Weight; Cadmium; Carotenoids; Catalase; Kidney; Lipid Peroxidation; Lycopene; Male; Nitric Oxide; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha; Weight Loss; Xanthine Oxidase

The present study was to investigate the effects of l-arginine (l-Arg) supplementation on cardiac oxidative stress and the inflammatory response in rats following acute exhaustive exercise on a treadmill. Rats were randomly divided into four groups: sedentary control (SC); SC with l-Arg treatment (SC+Arg); exhaustive exercise (E); exhaustive exercise with l-Arg treatment (E+Arg). Rats in groups SC+Arg and E+Arg received a 2 % l-Arg diet. Rats in groups E and E+Arg performed an exhaustive running test on a treadmill at a final speed of 30 m/min, 10 % grade, at approximately 70-75 % VO2max. The results showed a significant increase in cardiac xanthine oxidase (XO) and myeloperoxidase activities and membrane lipid peroxidation endproduct (malondialdehyde; MDA) levels of exercised rats compared with SC rats. The increased cardiac XO activity and MDA levels in exercised rats were significantly decreased in exercised rats supplemented with l-Arg. Myocardial GSSG content increased whereas the GSH:GSSG ratio was depressed in exercised rats compared with SC rats. Cardiac GSSG levels significantly decreased, whereas total glutathione, GSH and the GSH:GSSG ratio increased in exercised rats supplemented with l-Arg compared with exercised rats. The activities of creatinine kinase (CK) and lactate dehydrogenase (LDH), and lactate, uric acid, and nitrite and nitrate levels in the plasma significantly increased in exercised rats compared with SC rats. The activities of plasma CK and LDH were significantly decreased in l-Arg-supplemented plus exercised rats compared with exercised rats. These findings suggest that l-Arg supplementation reduces the oxidative damage and inflammatory response on the myocardium caused by exhaustive exercise in rats.

Topics: Animals; Antioxidants; Arginine; Blood Chemical Analysis; Body Weight; Dietary Supplements; Glutathione; Lipid Peroxidation; Male; Myocardium; Oxidation-Reduction; Oxidative Stress; Peroxidase; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Obesity frequently leads to the development of hypertension. We hypothesized that high-fat diet (HFD)-induced obesity impairs the endothelium-dependent dilation of arterioles. Male Wistar rats were fed with normal (control) or HFD (60% of saturated fat, for 10 wk). In rats with HFD, body weight, mean arterial blood pressure, and serum insulin, cholesterol, and glucose were elevated. In isolated gracilis muscle arterioles (diameter: approximately 160 microm) of HFD, rat dilations to ACh (at 1 microM, maximum: 83 +/- 3%) and histamine (at 10 microM, maximum: 16 +/- 4%) were significantly (P < 0.05) decreased compared with those of control responses (maximum: 90 +/- 2 and 46 +/- 4%, respectively). Dilations to the NO donor sodium nitroprusside were similar in the two groups. Inhibition of NO synthesis by N(omega)-nitro-l-arginine methyl ester reduced ACh- and histamine-induced dilations in control arterioles but had no effect on microvessels of HFD rats. The superoxide dismutase mimetic Tiron or xanthine oxidase inhibitor allopurinol enhanced ACh (maximum: 90 +/- 2 and 93 +/- 2%, respectively)- and histamine (maximum: 30 +/- 7 and 37 +/- 8%, respectively)-induced dilations in HFD arterioles, whereas the NAD(P)H oxidase inhibitor apocynin had no significant effect. Correspondingly, in carotid arteries of HFD rats, an enhanced superoxide production was shown by lucigenin-enhanced chemiluminescence, in association with an increased xanthine oxidase, but not NAD(P)H oxidase activity. In addition, a marked xanthine oxidase immunostaining was detected in the endothelial layer of the gracilis arterioles of HFD, but not in control rats. These findings suggest that, in obese rats, NO mediation of endothelium-dependent dilation of skeletal muscle arterioles is reduced because of an enhanced xanthine oxidase-derived superoxide production. These alterations demonstrate substantial dysregulation of arteriolar tone by the endothelium in HFD-induced obesity, which may contribute to disturbed tissue blood flow and development of increased peripheral resistance.

Topics: Acetylcholine; Animals; Arterioles; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Dietary Fats; Dose-Response Relationship, Drug; Insulin; Male; Muscle, Skeletal; Nitric Oxide; Rats; Rats, Wistar; Superoxides; Vasodilation; Xanthine Oxidase

To investigate if increased lipid peroxidation is involved in hypercholesterolemia-induced hypertension and renal injury, we examined the effects of allopurinol, a xanthine oxidase inhibitor, on these conditions. Groups of male Sprague--Dawley rats were fed for 8 weeks with a high-cholesterol diet (4% cholesterol), a high-cholesterol plus allopurinol (10 mg/kgBW/day) diet or a normal diet. Systolic blood pressure (SBP), serum lipids, uric acid (UA) and malondialdehyde (MDA) as a measure of lipid peroxides, and urinary excretion of protein (UP) were measured after 0, 4 and 8 weeks. Urinary excretion of nitrite plus nitrate (UNOx) and iron (UFe), and MDA in the kidney were measured after 8 weeks. The renal injury was evaluated by the glomerular sclerosis score (SS). The high-cholesterol diet increased SBP, serum total cholesterol and UA, MDA in the serum and kidney, UP, UNOx, UFe and SS. Allopurinol ameliorated cholesterol-induced elevation in serum UA, MDA in the serum and kidney, UP, UNOx, UFe and SS, but did not affect SBP. Hence, our results suggest that lipid peroxidation may be involved in hypercholesterolemia-induced renal injury, and that suppression of lipid peroxidation can reduce such injury.

Topics: Allopurinol; Animals; Blood Pressure; Body Weight; Cholesterol; Creatinine; Enzyme Inhibitors; Heart Rate; Hemodynamics; Hypercholesterolemia; Hypertension; Iron; Kidney; Kidney Diseases; Kidney Function Tests; Male; Malondialdehyde; Nitric Oxide; Proteinuria; Rats; Rats, Sprague-Dawley; Triglycerides; Uric Acid; Xanthine Oxidase

Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is accompanied by increased oxidative stress. This study examines the enzymatic source of reactive oxygen species in ACTH-hypertension.. Male Sprague-Dawley rats were divided into 10 groups of 10-20 rats per group. The NAD(P)H oxidase inhibitor apocynin (1.5 mmol/L in drinking water) or the xanthine oxidase inhibitor allopurinol (200 mg/kg/day via food) were administered daily. After 4 days, rats were co-administered ACTH (0.2 mg/kg/day) or saline by subcutaneous injection daily for 11 days (prevention study). In a reversal study, ACTH/saline was administered for 13 days and from day 8, apocynin or allopurinol was added for 5 days. Systolic blood pressure (SBP) was measured by the tail-cuff method and oxidative stress using plasma F2-isoprostane concentrations. Results were expressed as mean+/-SEM.. ACTH increased SBP (P<.001) but apocynin or allopurinol alone had no effect. Apocynin (but not allopurinol) co-treatment prevented (142+/-3 ACTH, 120+/-4 mm Hg apocynin+ACTH, P'<0.001) and reversed ACTH-induced hypertension (133+/-4 to 118+/-5 mm Hg, P<.05). Plasma F2-isoprostane concentrations were increased in ACTH-treated rats compared with saline (11.9+/-1.0 vs 8.2+/-0.8 nmol/L, P<.01), and apocynin attenuated the ACTH-induced rise in plasma F2-isoprostane concentrations. Serum urate concentrations were undetectable in 75% of rats treated with allopurinol and were not affected by ACTH.. Apocynin but not allopurinol prevented and reversed ACTH-induced hypertension in the rat. These results suggest superoxide production through NAD(P)H oxidase plays a role in ACTH-induced hypertension.

Topics: Acetophenones; Adrenocorticotropic Hormone; Allopurinol; Animals; Antihypertensive Agents; Antioxidants; Aorta, Thoracic; Blood Pressure; Body Weight; Enzyme Inhibitors; Hypertension; Isoprostanes; Male; NADPH Oxidases; Organ Size; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxides; Thymus Gland; Uric Acid; Xanthine Oxidase

Tissue homeostasis is determined by the balance between oxidants and antioxidants. Catalase is an important antioxidant enzyme regulating the level of intracellular hydrogen peroxide and hydroxyl radicals. The effect of catalase deficiency on renal tubulointerstitial injury induced by unilateral ureteral obstruction (UUO) has been studied in homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) compared with wild-type mice (C3H/AnLCs(a)Cs(a)). Complete UUO caused interstitial cell infiltration, tubular dilation and atrophy, and interstitial fibrosis with accumulation of type IV collagen in obstructed kidneys (OBK) of both mouse groups. However, the degree of injury showed a significant increase in OBK of acatalasemic mice compared with that of wild-type mice until day 7. The deposition of lipid peroxidation products including 4-hydroxy-2-hexenal, malondialdehyde, and 4-hydroxy-2-nonenal was severer in dilated tubules of acatalasemic OBK. Apoptosis in tubular epithelial cells significantly increased in acatalasemic OBK at day 4. Expression of caspase-9, a marker of mitochondrial pathway-derived apoptosis, increased in dilated tubules of acatalasemic mice. The level of catalase activity remained low in acatalasemic OBK until day 7 without compensatory upregulation of glutathione peroxidase activity. The data indicate that acatalasemia exacerbated oxidation of renal tissue and sensitized tubular epithelial cells to apoptosis in OBK of UUO. This study demonstrates that catalase deficiency enhanced tubulointerstitial injury and fibrosis in a murine model of UUO and thus supports the protective role of catalase in this model.

Topics: Acatalasia; Animals; Apoptosis; Body Weight; Catalase; Epithelial Cells; Fibrosis; Glutathione Peroxidase; Immunohistochemistry; In Situ Nick-End Labeling; Kidney Tubules; Male; Malondialdehyde; Mice; Mice, Inbred C3H; Mice, Knockout; Microscopy, Electron; Nephritis, Interstitial; Organ Size; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Ureteral Obstruction; Xanthine Oxidase

The effect of Wen-Pi-Tang extract on influenza virus infection in mice was investigated. The administration of Wen-Pi-Tang extract at a dose of 100mg/kg body wt. for 8 consecutive days to influenza virus-infected mice reversed the lack of body wt. gain and prevented the increase in lung weight caused by the infection in comparison with uninfected mice, while allopurinol, a xanthine oxidase (XOD) inhibitor, did not show these effects. The serum levels of uric acid and allantoin in influenza virus-infected mice were reduced by Wen-Pi-Tang extract administration. Moreover, Wen-Pi-Tang extract reduced the uric acid level more as the dose increased, although it exerted lower activity than allopurinol. The XOD activity of the lungs was elevated by influenza virus infection, but Wen-Pi-Tang extract administration inhibited this activity, indicating prevention of lung damage by oxygen free radicals generated by XOD. After the administration of Wen-Pi-Tang extract to influenza virus-infected mice, the lung superoxide dismutase activity was not significantly different from that of uninfected mice, whereas lung catalase activity was lower in the former than the latter, but slightly higher than that of influenza virus-infected mice, suggesting that Wen-Pi-Tang extract may prevent the generation of highly toxic hydroxyl radicals in the lung. In addition, the administration of both Wen-Pi-Tang extract and allopurinol reduced the degree of lung consolidation caused by influenza virus infection. In particular, Wen-Pi-Tang extract reduced the consolidation score in a dose-dependent manner and more markedly than allopurinol did. This study suggests that Wen-Pi-Tang extract could improve pathological conditions of the lungs induced by influenza virus infection.

Topics: Allantoin; Allopurinol; Animals; Body Weight; Catalase; Drugs, Chinese Herbal; Influenza A virus; Lung; Male; Mice; Mice, Inbred ICR; Molecular Structure; Orthomyxoviridae Infections; Oxidative Stress; Superoxide Dismutase; Uric Acid; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Animals; Body Weight; Dogs; Female; Glutathione; Hepatectomy; Hypertonic Solutions; Insulin; Ischemia; Liver; Liver Transplantation; Male; Organ Preservation; Organ Preservation Solutions; Raffinose; Reperfusion; Time Factors; Tissue and Organ Harvesting; Transplantation, Autologous

To investigate the effect of exercise on brain antioxidant status of diabetic rats.. Wistar rats were divided into four groups: Control (C), exercise (CE), diabetic (D), and diabetic+exercise (DE). Diabetes was induced by single administration of streptozotocin (60 mg/kg). We used an aerobic exercise program for 8 weeks of CE and DE rats. After the end of the experimental period, Cu, Zn-superoxide dismutase (Cu, Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), xanthine dehydrogenase (XDH) and xanthine oxidase (XO) activities and thiobarbituric acid reactive substances (TBARS) levels of brain were measured.. Diabetes caused significant reduction of brain Cu, Zn-SOD and GSH-Px activities in the D and DE groups. CAT activity was decreased only in the D group. Exercise did not alter CAT activity of brain, whereas markedly increased Cu, Zn-SOD activity in the DE group. In contrast to diabetes-related decrease in the activity of Cu, Zn-SOD, increase in the XO and GSH-Px activities were observed in the DE group compared with the D group. XDH activity was significantly reduced in two exercise groups according to the control rats, but the decrease was not accompanied with the activity of XO elevation in all groups. Increase in the XO activity and decrease in the XDH activity in the DE rats have revealed that diabetes and exercise have potentially effect in free radical production. On the other hand, TBARS levels were found to be elevated in all diabetic animals.. Our results show that aerobic exercise did not affect lipid peroxidation of brain, but in diabetic condition improved antioxidant defence.

Topics: Animals; Antioxidants; Body Weight; Brain; Catalase; Diabetes Mellitus, Experimental; Energy Intake; Glutathione Peroxidase; Male; Physical Conditioning, Animal; Rats; Rats, Wistar; Reference Values; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthine Dehydrogenase; Xanthine Oxidase

Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism occurring in most cell types. However, this housekeeping gene is expressed at very high levels in a number of mammalian tissues including the lactating mammary epithelium, suggesting additional roles for XOR in these tissues. Mice with targeted disruption of XOR were generated to assess these potential additional roles. XOR-/- mice are runted and do not live beyond 6 wk of age. Strikingly, however, XOR+/- females, although of healthy appearance and normal fertility, are unable to maintain lactation and their pups die of starvation 2 wk postpartum. Histological and whole-mount analyses showed that in XOR+/- females the mammary epithelium collapses, resulting in premature involution of the mammary gland. Electron microscopy showed that XOR is specifically required for enveloping milk fat droplets with the apical plasma membrane prior to secretion from the lactating mammary gland. We present evidence that XOR may have primarily a structural role, as a membrane-associated protein, in milk fat droplet secretion and thus XOR provides another example of "gene sharing". About 5% of women experience primary lactation insufficiency. The above observations suggest that human females suffering from xanthinuria, a deficiency in XOR, are potential candidates for lactation problems.

Topics: Animals; Body Weight; Cell Differentiation; Cell Membrane; DNA Primers; Epithelium; Female; Glycolipids; Glycoproteins; Heterozygote; Homozygote; Lactation; Lipid Droplets; Mammary Glands, Animal; Mice; Mice, Knockout; Microscopy, Electron; Polymerase Chain Reaction; Xanthine Oxidase

University of Wisconsin solution (UW) provides effective heart preservation under hypothermic conditions, but it can be deleterious at warmer temperatures. Re-warming during the implantation of the graft may be a problem. This study examined the damaging effect of peri-operative warm ischemia in a transplant setting and recovery from such damage. The amelioration of damage by rinsing the graft before re-warming and transplantation was also examined.. Rat donor hearts were preserved for 2 hr (0 degrees C) as follows: Series A was preserved with colloid-free UW (MUW), St. Thomas' solution (ST), or calcium-supplemented MUW (MUW+Ca) followed by either transplantation or warming (22 degrees C) for 10 min before transplantation. Series B was preserved with MUW, rinsed with fresh MUW, ST, MUW+Ca, or low-potassium MUW before warming and transplantation. All heart isografts were transplanted heterotopically with an indwelling left intraventricular balloon-tipped catheter. Graft function was measured 1 and 7 days after transplantation.. Grafts re-warmed rapidly during implantation. Function (left ventricular developed pressure, contractility, and relaxation) was significantly and persistently diminished in MUW-preserved grafts subjected to additional warming before transplantation. Preservation with ST was less effective than MUW despite being unaffected by warming. Preservation with MUW+Ca and rinsing with fresh MUW or ST before re-warming allowed recovery of function within 7 days despite significantly diminished function on day 1.. This study demonstrated that an increase in the peri-transplant warm ischemic period was detrimental when hearts were preserved with MUW. Preservation with calcium-supplemented MUW or rinsing the heart with fresh MUW or ST before transplantation ameliorated this damage.

Topics: Adenosine; Allopurinol; Animals; Blood Pressure; Body Weight; Cardioplegic Solutions; Glutathione; Graft Survival; Heart Transplantation; Insulin; Male; Myocardial Contraction; Myocardial Ischemia; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Inbred Strains; Time Factors; Transplantation, Isogeneic

Although oxygen-derived free radicals are known to play a role in cell injury and DNA alterations, the role of active oxidants in chronic pancreatitis has not been fully elucidated. Using WBN/Kob rats, which spontaneously develop chronic pancreatitis-like lesions, we investigated whether xanthine oxidase (XOD)-derived oxygen radicals are involved in pancreatic tissue injury.. WBN/Kob rats were fed a control or a tungsten diet. The latter depletes XOD activity. Histologic al changes, glutathione (GSH) content and XOD and superoxide dismutase (SOD) activities were determined in pancreatic tissue. Pancreatic 8-hydroxy-deoxyguanosine (8-OH-dG) levels and lithostathine mRNA were also examined.. In WBN/Kob rats, parenchymal destruction and fibrosis developed at approximately 12 weeks of age and progressed with each month. The activity of XOD was significantly higher in the early period (8-12 weeks), whereas the levels of GSH and SOD decreased after 16 weeks. Levels of 8-OH-dG in WBN/Kob rats were significantly elevated at 16 weeks. Lithostathine mRNA levels started to increase at 8 weeks, but were suppressed at 16 weeks. The tungsten diet significantly attenuated the histological changes in WBN/Kob rats. The increase in pancreatic XOD activity and 8-OH-dG content in WBN/Kob rats was significantly inhibited by the tungsten diet and lithostathine mRNA levels remained high at 16 weeks.. These results suggest that oxygen radicals generated by XOD play an important role in oxidative DNA damage and the development of chronic pancreatic injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amylases; Animals; Body Weight; Calcium-Binding Proteins; Chronic Disease; Deoxyguanosine; Glutathione; Lithostathine; Nerve Tissue Proteins; Pancreas; Pancreatitis; Procollagen-Proline Dioxygenase; Rats; Rats, Inbred Strains; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase; Xanthine Oxidase

Uric acid has been hypothesized as being one of the more important antioxidants in limiting the accumulation of glycosylated endproducts in birds. Study 1 was designed to quantitatively manipulate the plasma concentrations of uric acid using hemin and allopurinol while study 2 determined their effects on skin pentosidine, the shear force value of Pectoralis major muscle, plasma glucose, body weight and chemiluminescence monitored oxidative stress in broiler chickens. Hemin was hypothesized to raise uric acid concentrations thereby lowering oxidative stress whereas allopurinol was hypothesized to lower uric acid concentrations and raise measures of oxidative stress. In study 1 feeding allopurinol (10 mg/kg body weight) to 8-week-old broiler chicks (n=50) for 10 days decreased plasma uric acid by 57%. However, hemin (10 mg/kg body weight) increased uric acid concentrations 20%. In study 2, 12-week-old broiler chicks (n=90) were randomly assigned to either an ad libitum (AL) diet or a diet restricted (DR) group. Each group was further divided into three treatments (control, allopurinol or hemin fed). Unexpectedly, hemin did not significantly effect uric acid concentrations but increased (P<0.05) measures of chemiluminescence dependent oxidative stress in both the DR and AL birds probably due to the ability of iron to generate oxygen radicals. Allopurinol lowered concentrations of uric acid and increased (P<0.05) the oxidative stress in the AL birds at week 22, reduced (P<0.05) body weight in both the AL and DR fed birds at 16 and 22 weeks of age, and markedly increased (P<0.001) shear force values of the pectoralis major muscle. Skin pentosidine levels increased (P<0.05) in AL birds fed allopurinol or hemin fed birds, but not in the diet restricted birds at 22 weeks. The significance of these studies is that concentrations of plasma uric acid can be related to measures of oxidative stress, which can be linked to tissue aging.

Topics: Aging; Allopurinol; Animals; Antimetabolites; Arginine; Blood Glucose; Body Weight; Chickens; Cross-Linking Reagents; Diet; Glycation End Products, Advanced; Glycosylation; Hemin; Luminescent Measurements; Lysine; Muscle, Skeletal; Oxidative Stress; Skin; Uric Acid

The mechanisms responsible for the neurotoxic effects of Al remain poorly understood. In order to determine whether Al promotes oxidative stress in vivo, we measured the enzymatic activity of xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione-S-transferase (GST) and glutathione reductase (GR) in four groups of rats after eight days of intraperitoneal administration of variable concentrations of Al (0, 5, 10, and 15 mg/kg body weight, respectively). XO activity was measured in both plasma and liver samples, and the activities of the remaining enzymes were further determined in the brain and red blood cells (RBC). The most significant changes were observed in XO and GPX activities, that were enhanced and depressed, respectively. In both instances, the enzyme activities were correlated with Al concentrations, either positively (XO) or negatively (GPX). Enhancement of XO and inhibition of GPX activity may lead to the accumulation of intermediate toxic compounds such as hydrogen peroxide and hydroxyl radicals, since SOD activity is increased as well. The latter finding must be taken with some caution because previous studies have shown contradictory results in this field. Our data suggest that Al toxicity could be mediated by its action on both pro- and anti-oxidant enzymes. The biological significance of these findings remains to be established.

Topics: Aluminum; Animals; Antioxidants; Body Weight; Brain; Dose-Response Relationship, Drug; Erythrocytes; Free Radicals; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Xanthine Oxidase

Free radical formation caused by chronic ethanol administration could activate transcription factors such as nuclear factor-kappaB (NF-kappaB), which regulates production of inflammatory cytokines. Xanthine oxidase is one potential source of reactive oxygen species. Therefore, the purpose of this study is to determine whether allopurinol, a xanthine oxidase inhibitor and scavenger of free radicals, would affect free radical formation, NF-kappaB activation, and early alcohol-induced liver injury in rats. Male Wistar rats were fed a high-fat diet with or without ethanol (10-16 g/kg/day) continuously for up to 4 weeks with the Tsukamoto-French enteral protocol. Either allopurinol or saline vehicle was administered daily. Allopurinol had no effect on body weight or the cyclic pattern of ethanol in urine. Mean urine ethanol concentrations were 271 +/- 38 and 252 +/- 33 mg/dl in ethanol- and ethanol + allopurinol-treated rats, respectively. In the control group, serum aspartate aminotransferase and alanine aminotransferase levels were approximately 40 I.U./l and 25 U/l, respectively. Administration of enteral ethanol for 4 weeks increased serum transaminases approximately 5-fold. Allopurinol blunted these increases significantly by approximately 50%. Ethanol treatment also caused severe fatty infiltration, mild inflammation, and necrosis. These pathological changes also were blunted significantly by allopurinol. Furthermore, enteral ethanol caused free radical adduct formation, values that were reduced by approximately 40% by allopurinol. NF-kappaB binding was minimal in the control group but was increased significantly nearly 2.5-fold by ethanol. This increase was blunted to similar values as control by allopurinol. These results indicate that allopurinol prevents early alcohol-induced liver injury, most likely by preventing oxidant-dependent activation of NF-kappaB.

Topics: Alanine Transaminase; Allopurinol; Animals; Aspartate Aminotransferases; Bile; Body Weight; Central Nervous System Depressants; Diet; Electrophoresis; Enzyme Inhibitors; Ethanol; Free Radical Scavengers; Liver; Liver Diseases, Alcoholic; Male; NF-kappa B; Nuclear Proteins; Rats; Rats, Wistar; Xanthine Oxidase

The effects of alloxan diabetes and subsequent treatment with insulin on extra-mitochondrial oxygen metabolism in terms of D-amino acid oxidase (DAAO), xanthine oxidase and catalase were examined. The DAAO activity in the liver with D-alanine and D-serine decreased by 33-62% in the diabetic group while the decrease in the kidneys was 61-74%. Insulin treatment resulted in overstimulation of DAAO activity in the liver but not in the kidneys. Tissue glycogen content was lowered in the diabetic animals but was restored by insulin treatment. Tissue glycogen content and DAAO activity showed an inverse relationship. The xanthine oxidase activity in the two tissues decreased from 40-55%; the catalase activity decreased from 34-54%. Insulin treatment was unable to restore the xanthine oxidase and catalase activities in both the tissues.

Topics: Alloxan; Animals; Body Weight; Catalase; D-Amino-Acid Oxidase; Diabetes Mellitus, Experimental; Energy Metabolism; Hypoglycemic Agents; Insulin; Kidney; Liver; Male; Mitochondria; Oxygen Consumption; Rats; Rats, Wistar; Urine; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Animals; Bile; Blood Glucose; Body Weight; Fasting; Fatty Liver; Glutathione; Insulin; Liver Transplantation; Nutritional Status; Organ Preservation Solutions; Organ Size; Raffinose; Rats; Rats, Sprague-Dawley; Time Factors; Tissue Donors; Transplantation, Homologous; Treatment Outcome

Xanthine oxidase is a highly versatile enzyme which is widely distributed among various species. Though the presence of the enzyme in serum is not yet established, high antibody titre of this enzyme has been reported. Xanthine oxidase is thought to be the principal source of free radical generation via degradation of nucleotides to the end product, uric acid. The aim of this study was to detect xanthine oxidase activity in human plasma and report any significant relationships found between its activity and variables such as race, age and sex for the sample size studied. Forty six normal healthy individuals (14 males and 32 females) were studied. The enzyme activity was measured by a spectrophotometric method whereby the reduction of ferricytochrome c by free radicals was calculated and expressed as nmol O2 production/ml/min. Results obtained showed that there was a positive relationship between xanthine oxidase activity with age (r = 0.415, p < 0.05) and weight (r = 0.369, p < 0.05) in the normal individual. For the age group 30-39 yrs (n = 11), a higher enzyme activity was observed in males (2.71 +/- 1.44) as compared to females (2.34 +/- 1.23) but it was not significant (p = 0.53). For racial distribution, the Malays [M] have a higher enzyme activity (2.65 +/- 0.86, N = 32) than their Indian [I] (2.27 +/- 0.58; N = 7) and Chinese counterparts [C] (1.44 +/- 1.22; N = 7) but this was also not statistically significant (M vs I: p = 0.39; M vs C: p = 0.07; I vs C: p = 0.16). In conclusion this study showed that there is a measurable amount of xanthine oxidase activity in the human plasma.

Topics: Adult; Age Factors; Body Weight; Female; Humans; Male; Sex Factors; Xanthine Oxidase

The modifying effect of dietary administration of a xanthine oxidase inhibitor 1'-acetoxychavicol acetate (ACA) present in an edible plant Languas galanga in Thailand on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in rats. Male F344 rats were given s.c. injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce colonic ACF. They were fed the diets containing 100 or 200 ppm ACA for 5 weeks, starting 1 week before the first dosing of AOM. At the termination of the study (week 5), AOM induced 118 +/- 28 ACF/colon. Dietary administration of ACA caused significant reduction in the frequency of ACF (41% inhibition by 100 ppm ACA feeding and 37% inhibition by 200 ppm ACA feeding, P<0.01). Such inhibition might be associated with suppression of the proliferation biomarkers' expression such as ornithine decarboxylase activity in the colonic mucosa, number of silver-stained nucleolar organizer regions' protein in the colonic mucosal cell nuclei and blood polyamine content. These results indicate that ACA could inhibit the development of AOM-induced ACF through its suppression of cell proliferation in the colonic mucosa and ACA might be a possible chemopreventive agent against colon tumourigenesis.

Topics: Animals; Antineoplastic Agents; Azoxymethane; Benzyl Alcohols; Body Weight; Cell Division; Colon; Colonic Diseases; Enzyme Inhibitors; Intestinal Mucosa; Liver; Male; Organ Size; Ornithine Decarboxylase; Polyamines; Precancerous Conditions; Rats; Rats, Inbred F344; Terpenes; Xanthine Oxidase

In the present study we have attempted to suppress the formation of megamitochondria by scavengers for free radicals since conditions for the formation of megamitochondria are often intimately related to the generation of free radicals. We employed three different experimental conditions to induce megamitochondria in the liver: ethanol, hydrazine and chloramphenicol (CP). Scavengers for free radicals tested were: alpha-tocopherol, coenzyme Q10(CoQ10) and 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl(4-OH-TEMPO). Allopurinol (AP), a xanthine oxidase inhibitor, was also tested. Results obtained were as follows. (1) Changes observed in the liver of animals treated with ethanol, hydrazine or CP were: formation of megamitochondria; decreases in the body weight and the weight of the liver; remarkable increases in the level of lipid peroxidation; increases in the activity of xanthine oxidase. (2) 4-OH-TEMPO was most effective in improving these changes. A mechanism of the formation of megamitochondria is proposed stressing the role of free radicals in the mechanism.

Topics: Allopurinol; Animals; Body Weight; Chloramphenicol; Coenzymes; Cyclic N-Oxides; Depression, Chemical; Enzyme Inhibitors; Ethanol; Free Radical Scavengers; Hydrazines; Lipid Peroxidation; Male; Malondialdehyde; Membrane Fusion; Mitochondria, Liver; Purines; Rats; Rats, Wistar; Spin Labels; Ubiquinone; Vitamin E; Xanthine Oxidase

Correlation between chloramphenicol-induced formation of megamitochondria in the mouse liver and oxidative stress was studied by lipid peroxidation analysis and electron microscopic technique. Chloramphenicol suppressed increases in the body weight and liver weight of experimental animals and at the same time induced a remarkable increase in lipid peroxidation in the liver during the formation of megamitochondria. A spin trapping agent, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, abolished all these changes induced by chloramphenicol. Namely, both the body weight and liver weight of chloramphenicol-treated animals stayed at the same levels as those of the control, and the formation of megamitochondria was completely suppressed. Allopurinol, a xanthine oxidase (EC 1.2.3.2) inhibitor, partly inhibited the changes induced by chloramphenicol, as described above. These results suggest that chloramphenicol-induced formation of megamitochondria is not simply ascribed to the suppression of the dividing process of mitochondria due to lowered protein synthesis in mitochondria but is intimately related to oxidative stress. Furthermore, the results obtained with allopurinol may indicate that enhanced levels of lipid peroxidation observed in chloramphenicol-treated animals are partly due to enhanced rate of the degradation of purine nucleotides catalyzed by xanthine oxidase.

Topics: Allopurinol; Animals; Body Weight; Chloramphenicol; Enzyme Inhibitors; Lipid Peroxidation; Liver; Male; Mice; Microscopy, Electron; Mitochondria, Liver; Mitochondrial Swelling; Organ Size; Piperidines; Protein Synthesis Inhibitors; Purine Nucleotides

Hyperthyroidism induces a number of metabolic and physiological changes in the heart including hypertrophy, increase in inotropic status, and alterations of myocardial energy metabolism. The effects of hyperthyroidism on adenosine metabolism which is intimately involved in the control of many aspects of myocardial energetics, have not been clarified. The aim of this study was thus to evaluate the potential role of adenosine in the altered physiology of the hyperthyroid heart. Transport of adenosine was studied in cardiomyocytes isolated from hyperthyroid and euthyroid rats. Activities of different enzymes of purine metabolism were studied in heart homogenates and concentrations of nucleotide and creatine metabolites were determined in hearts freeze-clamped in situ. Both transport of adenosine into cardiomyocytes and the rate of intracellular phosphorylation were higher in the hyperthyroid rat. At 10 microM concentration, adenosine transport rates were 275 and 197 pmol/min/mg protein in hyperthyroid and euthyroid cardiomyocytes respectively whilst rates of adenosine phosphorylation were 250 and 180 pmol/min/mg prot. An even more pronounced difference was observed if values were expressed per number of cells due to cardiomyocyte enlargement. Hyperthyroidism was associated with a 20% increase in adenosine kinase, 30% decrease in membrane 5'-nucleotidase and 15% decrease in adenosine deaminase activities measured in heart homogenates. In addition there was a substantial depletion in the total creatine pool from 63.7 to 41.6 mumol/g dry wt, a small decrease in the adenylate pool (from 27.2 to 24.3 mumol/g dry wt) and an elevation of the guanylate pool (from 1.22 to 1.36). These results show that adenosine transport and phosphorylation capacity is enhanced in hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenine; Adenosine; Adenosine Deaminase; Adenosine Kinase; Adenosylhomocysteinase; AMP Deaminase; Animals; Biological Transport; Body Weight; Disease Models, Animal; Heart; Hydrolases; Hyperthyroidism; Male; Myocardium; Nucleotidases; Organ Size; Phosphorylation; Purine-Nucleoside Phosphorylase; Rats; Thyroxine; Time Factors; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Amylases; Animals; Body Weight; Cell Separation; Centrifugation, Density Gradient; Collagenases; Dogs; Glutathione; Insulin; Insulin Secretion; Islets of Langerhans; Organ Preservation Solutions; Pancreas; Raffinose; Tissue Preservation

The local hepatic disposition of BOF-4272, a newly developed xanthine oxidase (XO)/xanthine dehydrogenase (XDH) inhibitor, was evaluated in the rat perfusion system following pulse input of the drug into the portal vein. The elution time profiles from the liver into the hepatic vein were analyzed by dispersion models. The disposition of BOF-4272 through the rat liver was represented by a two-compartment dispersion model based on the Akaike's Information Criterion (AIC). The area under the concentration time curve (aucH) of BOF-4272 was proportional to the dosing amount, and the mean transit time was constant from 62.5 up to 500 micrograms/liver, which demonstrates that the local hepatic disposition of BOF-4272 is linear in this dosing range. The local disposition parameters were precisely estimated at the dosing amount of 250 micrograms/liver using several rats. These parameters in the dispersion model were correlated to the local moment characteristics. The hepatic recovery ratio (FH) was 22.8 +/- 3.2% and the mean transit time (tH) was 0.112 +/- 0.008 min, which show that the influx of BOF-4272 into the liver is efficiently large.

Topics: Animals; Body Weight; In Vitro Techniques; Liver; Male; Models, Biological; Organ Size; Perfusion; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet; Triazines; Xanthine Dehydrogenase; Xanthine Oxidase

The role of oxidant release and tissue antioxidant defenses on inflammation-induced organ injury is not clearly defined.. We determined the effect of acute zymosan peritonitis in rats on lung and liver tissue oxidant stress and antioxidant defenses during a 5-day period. Oxidant activity was measured as tissue malondialdehyde and oxidized glutathione (GSSG). Antioxidant activity was measured as tissue-reduced glutathione (GSH) and catalase activity. Rats were maintained hydrated with subcutaneous crystalloid. Animals were killed at 4, 12, and 24 hours and 5 days.. Acute peritonitis was evident at 12 and 24 hours but was resolving at 5 days. Peritoneal fluid cultures were negative after 24 hours. A 50% mortality rate was noted between 20 and 30 hours, with no deaths after 30 hours. We noted a significant increase in lung GSSG and malondialdehyde at 4 hours that persisted for the 5 days, as did histologic evidence of a progressing severe lung inflammation. No increased conversion of lung xanthine dehydrogenase to xanthine oxidase was noted. Lung GSH and catalase activity were maintained at control despite negligible food intake. In contrast, liver GSSG was increased significantly only at the 4-hour period, corresponding with a transient conversion of xanthine dehydrogenase to xanthine oxidase from 10% to 31%. Tissue malondialdehyde did not increase despite the initial oxidant stress. However, tissue GSH and catalase values decreased by more than 50% after 24 hours and remained decreased at 5 days.. We conclude that early lung and liver oxidant stress is initiated by acute peritonitis. Lung oxidant changes persist and lung dysfunction progresses, even though antioxidant activity is maintained and acute peritonitis is resolving. Liver lipid peroxidation did not develop despite oxidant release, probably because of a large antioxidant reserve. However, a severe and sustained decrease in liver antioxidants results, increasing the potential damage from a subsequent oxidant insult.

Topics: Animals; Antioxidants; Body Weight; Catalase; Diuresis; Glutathione; Glutathione Disulfide; Hematocrit; Liver; Lung; Male; Oxidants; Oxygen; Peritonitis; Rats; Rats, Wistar; Time Factors; Xanthine Dehydrogenase; Xanthine Oxidase; Zymosan

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB/Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.

Topics: Allopurinol; Animals; Body Weight; Diabetes Mellitus, Type 1; Diet; Female; Free Radical Scavengers; Male; Rats; Rats, Inbred BB; Thiourea; Tiopronin; Vitamin E; Weight Gain

The purpose of the present study was to determine the effects of chronic portal diversion on antioxidant levels in the rat liver. Male Sprague-Dawley rats (n = 32) were used for these studies. An end-to-side portacaval anastomosis was constructed in 17 of the rats. Sham-operated rats (n = 15) served as controls. Two weeks later, hepatic blood flow was measured by the radioactive microsphere technique and the liver was harvested for biochemical measurement of catalase, manganese superoxide dismutase, copper-zinc superoxide dismutase, selenium glutathione peroxidase, xanthine oxidase, xanthine dehydrogenase and reduced glutathione (acid soluble sulfhydryls). Total hepatic blood flow was approx. 40% lower in portacaval-shunted rats when compared to sham-operated control rats. Total superoxide dismutase (SOD) and xanthine dehydrogenase (XD) levels were significantly reduced in the liver of shunted rats when compared to controls. Xanthine oxidase activity was unaltered. The decreased superoxide dismutase levels were exclusively due to reductions in the cytosolic Ca/Zn SOD; Mn SOD levels were unaltered. These data are consistent with oxidant stress and suggest that the liver of subjects with conditions characterized by decreased portal blood flow may be more susceptible to oxidant-induced liver injury.

Topics: Animals; Antioxidants; Body Weight; Catalase; Glutathione; Glutathione Peroxidase; Isoenzymes; Liver; Liver Circulation; Male; Organ Size; Oxidants; Portacaval Shunt, Surgical; Rats; Rats, Inbred Strains; Reference Values; Regional Blood Flow; Superoxide Dismutase; Xanthine Dehydrogenase; Xanthine Oxidase

Repeated administration of carbon tetrachloride (CCl4) induces liver cirrhosis, possibly because it involves the production of free radicals. In order to evaluate the effect of free radical scavengers such as superoxide dismutase (SOD) and allopurinol in the pathogenesis of liver cirrhosis, rats were subjected to repeated CCl4 administration with and without scavengers. Four groups of animals were studied: CCl4 plus SOD (group 1), CCl4 plus allopurinol (group 2), CCl4 alone (group 3) and olive oil (group 4, normal controls). Analysis of plasma and tissue concentrations of trace elements was performed and histopathological patterns were studied in all groups after 7 weeks of repeated intraperitoneal administration of the solutions. Plasma levels of zinc and selenium were significantly lower in all experimental groups, with reciprocal elevation of manganese and copper. Copper and manganese content in the liver tissue was significantly higher in all three experimental groups. The zinc content was elevated in groups receiving CCl4 alone (group 3) or with allopurinol (group 2). The liver selenium, however, was significantly lower in these two groups. The copper:zinc ratio for plasma was 0.78 in the control group, 1.6 in the CCl4 group, 1.3 in the allopurinol group and 1.5 in the SOD group. For liver tissue, the ratio was 0.07 for controls, 0.17 for CCl4, 0.11 for allopurinol and 0.28 for the SOD group. The changes in trace element content correlated with the severity of cellular damage observed microscopically in the liver. The higher the copper:zinc ratio, the more advanced and extensive was the microscopic evidence of liver injury after CCl4 challenge.

Topics: Allopurinol; Animals; Body Weight; Carbon Tetrachloride; Disease Models, Animal; Liver Cirrhosis, Experimental; Male; Organ Size; Rats; Rats, Inbred Strains; Superoxide Dismutase; Trace Elements

Exhaustive endurance exercise in adult female albino rats (C-Ex) increased the generation of free radicals (R.) in the myocardium, probably through enhanced oxidative mechanisms. Free radical mediated lipid peroxidation measured in the form of tissue MDA content also increased in C-Ex animals, suggesting the exercise-induced oxidative stress in these animals. Dietary supplementation of Vit E, for a period of 60 days significantly increased Vit E incorporation into the serum and myocardium, more so in the myocardium. Vit E supplementation to exercising animals completely abolished the radical production. The protection of Vit E against oxidative stress appears to be not mediated through the improvement of antioxidant mechanisms by enzymes like SOD, catalase and Se-GSH Px. However the non Se-GSH Px, the enzyme involved in the reduction of endoperoxides increased significantly in control and Vit E fed animals in response to exercise. The protection of Vit E against exercise-induced oxidative stress was correlated with its multivarious activities like a) scavenger of free radicals; b) inhibition of lipoxygenases; and c) reduction of peroxides in association with lipoxygenases. These studies indicate that dietary supplementation of Vit E protects the animals from the possible oxidative damages of endurance exercise.

Topics: Animals; Body Weight; Female; Food, Fortified; Free Radicals; Heart; Lipid Peroxidation; Myocardium; Organ Size; Oxygen; Physical Exertion; Rats; Rats, Inbred Strains; Stress, Physiological; Superoxide Dismutase; Vitamin E; Xanthine Oxidase

In this prospective randomized trial a porcine model of renal autotransplantation was used to compare quality of preservation, as reflected by detailed analysis of posttransplant renal function, following 24-hr cold storage in phosphate-buffered sucrose (PBS140), hyperosmolar citrate (HOC), and University of Wisconsin (UW) preservation solutions. There were 6 deaths with primary nonfunction: 3 of 5 HOC, 2 of 5 UW, but only 1 of 5 PBS140. Analysis of the whole group and separate analysis of the survivors demonstrated significantly better renal function following preservation with PBS140 when compared with both HOC and UW, with a lower peak serum creatinine (P = 0.02) and improved loop of Henle function (P = 0.02). The animals in the PBS140 group also demonstrated a more rapid return to normal creatinine, higher GFR, improved tubular function, and higher effective renal plasma flow, with figures approaching statistical significance (P = 0.06-0.07). The proposal of UW as a universal storage medium prompted this study, and its results suggest the need for a clinical comparison of renal preservation using UW and PBS140 in a prospective randomized trial.

Topics: Adenosine; Allopurinol; Animals; Body Weight; Creatinine; Female; Glomerular Filtration Rate; Glutathione; Insulin; Kidney Transplantation; Organ Preservation; Organ Preservation Solutions; Organ Size; Raffinose; Solutions; Sugar Phosphates; Swine; Transplantation, Autologous

Naturally occurring quinones and quinone-containing extracts of seeds of the toxic plant Cassia obtusifolia (sicklepod) affected muscle mitochondrial function. Aqueous suspensions and organic extracts of C. obtusifolia seeds slightly elevated plasma creatine kinase levels of Sprague-Dawley rats. These extracts were analyzed by fused silica capillary gas chromatography and found to contain nine anthraquinones and three anthrones. Urinary metabolites primarily consisted of beta-glucuronide conjugates of the anthraquinones. The three anthrones or conjugate analogues were not present in the urine in detectable amounts. Emodin, doxorubicin and organic extracts of C. obtusifolia inhibited NADH:cytochrome c oxidoreductase activity of bovine heart mitochondrial particles and NADH:CoQ oxidoreductase activity of porcine heart mitochondrial NADH dehydrogenase, whereas juglone was stimulatory. Relative quinone metabolism correlated with semiquinone formation rate and with redox potential. A protective effect of coenzyme Q against enzyme inhibition by anthraquinones was also observed.

Topics: Animals; Anthraquinones; Body Weight; Cassia; Chromatography, Gas; Cytochrome Reductases; In Vitro Techniques; Male; Mitochondria, Muscle; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains; Xanthine Oxidase

The effects of molybdenum (Mo) supplementation in the drinking water at the levels of 0.1, 0.5, 1.0, 2.0, 5.0 and 10.0 mg/l on the hepatic trace element concentrations and enzyme activities of female Sprague-Dawley rats were studied. The mean hepatic Mo concentration increased significantly in the rats supplemented with 0.1 mg Mo/l as compared to the nonsupplemented rats, but a further significant increase did not occur until the supplementation level reached 5-10 mg Mo/l drinking water. Hepatic copper concentration of the group given 0.1 mg Mo/l and hepatic iron content of the groups given 0.1 or 0.5 mg Mo/l were significantly higher than those of the other groups. The hepatic xanthine dehydrogenase/oxidase activity was not significantly affected by Mo supplementation. The hepatic sulfite oxidase (SOX) activity of the group given 0.1 mg Mo/l was significantly higher than that of the nonsupplemented group. The SOX activities of all the other supplemented groups were at a significantly different level intermediate between the first two. The hepatic superoxide dismutase (SOD) activity was significantly higher in the group given 0.1 mg/l than in the other groups. These results indicated that molybdenum enzymes and SOD might not be participants in previously reported anticarcinogenic activity of Mo, as supplementation at the level of 0.1 mg/l had been observed to be inefficacious in inhibiting N-nitrosomethylurea-induced mammary tumor incidence.

Topics: Animals; Body Weight; Female; Liver; Molybdenum; Oxidoreductases Acting on Sulfur Group Donors; Rats; Superoxide Dismutase; Trace Elements; Water Supply; Xanthine Dehydrogenase; Xanthine Oxidase

Cardioprotectant effects of allopurinol were investigated in ethanol-fed poults during induction of cardiomyopathy and during a period of ethanol abstinence. In young poults fed ethanol, allopurinol has an additive effect on depression of growth but has little or no effect on caloric consumption. Allopurinol significantly depresses heart weight and heart weight to body weight ratios in young poults. In poults 5 weeks and older, allopurinol depresses significantly body weight and caloric consumption. Although allopurinol depresses heart weight in older poults, it appears to have little or no effect on heart weight to body weight ratios. Cardioprotective effect of allopurinol is more apparent during the inductive process than during the recovery phase.

Topics: Allopurinol; Animals; Body Weight; Cardiomyopathy, Alcoholic; Ethanol; Heart; Organ Size; Poultry Diseases; Turkeys

The effect of dietary iron on the development of copper-deficiency anemia in the growing rat was investigated. For up to 80 d, female rats (75 g) were fed purified diets containing adequate, marginal or low levels of iron, and either 0.7 or 10 ppm copper. Hemoglobin levels and factors postulated to affect liver iron mobilization, including ferroxidase (Fox) I and II, ascorbate and liver xanthine dehydrogenase (XDH) were assayed. By d 7, Fox I activity in the copper-deficient groups was 10% that of the copper-sufficient groups; thereafter, Fox I activity remained low, and was not affected by dietary iron. Fox II activity in the copper-deficient groups after d 28 was 50-75% of values from rats adequate in copper. On d 49, hemoglobin levels in the copper-deficient groups were lower than in the copper-sufficient groups fed low and marginal levels of iron, but were similar to those fed adequate iron. Liver iron was similar in both groups fed adequate iron, but was higher in the copper-deficient than in the copper-sufficient rats fed low or marginal levels of iron. Copper deficiency tended to result in slightly lower ascorbate levels on d 80 at all levels of iron. Liver XDH activity tended to be lower in the copper-deficient groups than in the copper-sufficient groups on d 28 and 49. These results show that copper deficiency may impair liver iron mobilization in the growing rat if dietary iron is low. Possible mechanisms include decreased Fox activity and/or decreased iron reduction by ascorbate or XDH.

Topics: Anemia; Animal Nutritional Physiological Phenomena; Animals; Ascorbic Acid; Body Weight; Ceruloplasmin; Copper; Diet; Drug Interactions; Female; Hematocrit; Hemoglobins; Iron; Kidney; Liver; Myocardium; Organ Size; Oxidoreductases; Rats; Rats, Inbred Strains; Spleen; Xanthine Dehydrogenase; Xanthine Oxidase; Zinc

In this study, allopurinol toxicity was investigated in the liver and the kidney in the rat. Allopurinol was intraperitoneally administered to rats, once a day, for 1, 3 or 10 days, in doses of 3, 10, 30 and 100 mg/kg body weight/day. At the 24th hour after the last administration, the rat was sacrificed, and blood and tissue samples were taken for analyses. In doses of 30 mg/kg/day and more, decreases of the body weight and the liver weight were observed, while the kidney weight increased. The plasma activities of alkaline phosphatase, glutamic oxaloacetic and glutamic pyruvic transaminases showed no increases, while the blood urea nitrogen and creatinine increased. These changes were the most remarkable in the 3 day administration, whereas they approached the control level thereafter. In doses of 10 mg/kg/day and less, no significant changes were observed in comparison to the control. These results denote that the minimal toxic dose ranges between 10 and 30 mg/kg/day, and that the kidney is more sensitive than the liver. In addition, these results also denote that the renal and hepatic failures are reversively restored even when allopurinol is further administered later than the 3 day. This fact suggests not only that the capacity inactivating allopurinol in the body is increased, but also that the enzymatic induction in the allopurinol inactivation system is accelerated.

Topics: Allopurinol; Animals; Blood Urea Nitrogen; Body Weight; Creatinine; Kidney; Liver; Male; Organ Size; Organ Specificity; Rats; Rats, Inbred Strains

Topics: Aged; Alcohol Drinking; Allopurinol; Blood Coagulation; Body Weight; Cholesterol; Cholesterol, HDL; Gout; Humans; Lipoproteins, HDL; Male; Middle Aged; Triglycerides

We studied the capacity of various chemicals to promote urinary bladder cancer in male F344 rats after initiation by N-nitroso-n-butyl-(4-hydroxybutyl)amine (BBN). The rats were given initially 0.01% BBN in the drinking-water for 4 wk and then the test compound in the diet for 34 wk. Effects were judged by measuring the formation of preneoplastic lesions papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder. Administration of 5%, but not 0.5% (w/w) sodium saccharin in the diet significantly increased the incidence and extent of PN hyperplasia. This finding could be related to the induction of cancers in the rat urinary bladder by high levels of saccharin. Sodium ascorbate (5%). DL-tryptophan (5%) and allopurinol (0.02%) also significantly increased the extent of PN hyperplasia in the affected animals, but other test chemicals, such as acetazolamide (0.35%) and quercetin (5%) did not. The results with sodium saccharin and DL-tryptophan were consistent with previous findings and suggest that sodium ascorbate and allopurinol have promoting activities in urinary bladder carcinogenesis in rats. No correlation was found between the extent of crystalluria and promotion of preneoplastic lesions.

Topics: Acetazolamide; Allopurinol; Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Hyperplasia; Male; Neoplasms, Experimental; Nitrosamines; Quercetin; Rats; Rats, Inbred F344; Saccharin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms

We analyzed Michaelis--Menten pharmacokinetic parameters of phenytoin with and without the coadministration of allopurinol (150 and 200 mg/day) in a child with Lesch--Nyhan syndrome. The Vmax and Km were estimated from at least two different sets of serum concentration--dosage data of phenytoin. The Vmax values (mg/kg/day) were 16.1 without allopurinol, and 12.4 and 10.9 with allopurinol (150 and 200 mg/day), respectively, whereas those for Km remained relatively constant (3.9 to 4.9 microgram/ml). Our results suggest that allopurinol is a drug that inhibits the hepatic metabolism of phenytoin.

Topics: Adolescent; Allopurinol; Body Weight; Child; Child, Preschool; Drug Interactions; Humans; Kinetics; Lesch-Nyhan Syndrome; Male; Phenytoin

Topics: Alcohol Drinking; Allopurinol; Blood Proteins; Body Weight; Coronary Disease; Diabetes Complications; Female; Gout; Humans; Hypertension; Lead Poisoning; Male; Protein Binding; Risk; Uric Acid; Urinary Calculi

Topics: Adenine; Allopurinol; Animals; Body Weight; Caseins; Dietary Proteins; Kidney; Kidney Diseases; Kidney Tubules; Liver; Male; Organ Size; Rats; Urine; Xanthine Oxidase

Molybdenum toxicity and the interactions between copper, molybdenum and sulphate are reviewed. The main signs of molybdenum poisoning are poor growth and anaemia (rat, chick, rabbit, cattle and sheep), anorexia (rat), diarrhoea and achromotrichia (cattle and sheep), joint and bone deformities (rat, rabbit, cattle), central nervous system degeneration and loss of crimp in wool (sheep). The following topics are discussed: (1) The effect of sulphate and sulphur compounds on molybdenum toxicity. (2) The effect of molybdenum on tissue copper levels. (3) The effect of molybdenum on the distribution of copper in plasma. (4) The effect of molybdenum on uptake and excretion of copper. (5) The possible existence of copper(II) molybdate in vivo. (6) The influence of molybdenum on sulphide production by ruminal micro-organisms. (7) Competition between molybdenum and sulphate in intestinal transport. (8) Interaction of sulphur with copper in vivo. (9) The possible involvement of molybdenum in gout and multiple sclerosis in humans.

Topics: Animals; Anorexia; Body Weight; Cattle; Chickens; Copper; Drug Interactions; Guinea Pigs; Molybdenum; Poisoning; Rabbits; Rats; Sheep; Species Specificity; Sulfates; Turkeys; Xanthine Oxidase

Effect of the administration of 4-hydroxypyrazolo([3,4-d]pyrimidine (allopurinol) on the growth of Ehrlich ascites tumor cells was investigated in an in vivo system. Oral administration of allopurinol (0.1% in diet) suppressed the growth of both ascites and solid types of the tumor after the implantation of Ehrlich tumor cells in mice. The inhibitory action depended on the dose but was lost repidly when the administration was interrupted. Possible mechanisms involved in the inhibitory effect of allopurinol on tumor growth were briefly discussed.

Topics: Allopurinol; Animals; Body Weight; Carcinoma, Ehrlich Tumor; Depression, Chemical; Dose-Response Relationship, Drug; Mice

Topics: Animals; Body Weight; Cycloheximide; Electron Spin Resonance Spectroscopy; Ileum; Kidney; Kinetics; Liver; Lung; Male; Molybdenum; Organ Size; Organ Specificity; Oxidoreductases; Puromycin; Rats; Sulfites; Tungsten; Vanadium; Xanthine Oxidase

Topics: Animals; Body Weight; Electron Spin Resonance Spectroscopy; Kidney; Liver; Male; Molybdenum; Oxidoreductases; Rats; Sulfites; Vanadium; Xanthine Oxidase

Topics: Adult; Aged; Alcohol Drinking; Allopurinol; Aspartate Aminotransferases; Body Height; Body Weight; Cholesterol; Gout; Humans; Hyperlipidemias; Liver; Male; Middle Aged; Obesity; Probenecid; Sulfobromophthalein; Triglycerides; Uric Acid

Topics: Adenine; Allopurinol; Body Weight; Child, Preschool; Chlorpromazine; Creatinine; Exchange Transfusion, Whole Blood; Humans; Language Development; Lesch-Nyhan Syndrome; Male; Motor Skills; Movement Disorders; Pedigree; Pentosyltransferases; Phenothiazines; Tetrabenazine; Uric Acid

Topics: Amino Acids; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Caseins; Dietary Fats; Dietary Proteins; Fatty Acids, Essential; Glucosephosphate Dehydrogenase; Glutens; Hexosephosphates; Liver; Liver Glycogen; Lysine; Male; Organ Size; Phosphogluconate Dehydrogenase; Proteins; Rats; Threonine; Triticum; Xanthine Oxidase; Zea mays

Topics: Agranulocytosis; Allopurinol; Animals; Blood Cell Count; Body Weight; Bone Marrow; Bone Marrow Cells; Drug Synergism; Hematopoiesis; Male; Mercaptopurine; Neutrophils; Rabbits

Topics: Animals; Body Weight; Glutamate Dehydrogenase; Guinea Pigs; Hydroxybutyrate Dehydrogenase; L-Lactate Dehydrogenase; Liver; Male; Vitamin E; Vitamin E Deficiency; Xanthine Oxidase

Topics: Alanine Transaminase; Animals; Arginase; Aspartate Aminotransferases; Body Weight; Chickens; Esterases; Hematocrit; Kidney; Liver; Male; Organ Size; Palmitic Acids; Pancreas; Vitamin A; Vitamin A Deficiency; Xanthine Oxidase

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Allopurinol; Animals; Body Weight; Hypoxia; Kidney; Rats

Topics: Administration, Oral; Allopurinol; Animals; Appetite; Body Weight; Carbon Radioisotopes; Castration; Diet; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Feedback; Guanine; Histocytochemistry; Kidney Function Tests; Male; Nitrogen; Osmolar Concentration; Pteridines; Purines; Pyrimidines; Swine; Testis; Time Factors; Urea

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Body Weight; Ceruloplasmin; Copper; Diet; Drug Antagonism; Fructose-Bisphosphate Aldolase; Glucosephosphate Dehydrogenase; Glycolysis; Lactates; Liver; Molybdenum; Rats; Succinate Dehydrogenase; Transferases; Xanthine Oxidase

Topics: Aging; Animals; Body Weight; Bone and Bones; Calcium; Environment; Female; Femur; Germ-Free Life; Intestines; Liver; Magnesium; Male; Metals; Organ Size; Phosphorus; Proteins; Rats; Xanthine Oxidase

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Erythrocytes; Female; Flavin-Adenine Dinucleotide; Glutathione Reductase; Liver; Male; Organ Size; Rats; Riboflavin; Riboflavin Deficiency; Thiamine Deficiency; Vitamin B 6 Deficiency; Xanthine Oxidase

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Creatinine; Diet; DNA; Evaluation Studies as Topic; Inosine; Liver; Male; Methods; Methylene Blue; NAD; Phosphorus; Proteins; Rats; Riboflavin Deficiency; Stimulation, Chemical; Thiamine Deficiency; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Animals; Body Weight; Chickens; Diet; Female; Growth; Hypoxanthines; Kidney; Liver; Male; Organ Size; Paralysis; Purines; Riboflavin Deficiency; Uric Acid; Xanthine Oxidase

Topics: Age Factors; Alanine Transaminase; Animal Nutritional Physiological Phenomena; Animals; Arginase; Aspartate Aminotransferases; Body Weight; Chickens; Dietary Proteins; Fluorescence; Glutens; Glycine max; Kidney; Liver; Male; Organ Size; Plant Proteins; Stimulation, Chemical; Xanthine Oxidase

Topics: Aging; Animals; Body Weight; Centrifugation; Dietary Proteins; Fluorometry; Kinetics; Liver; Male; Organ Size; Protein Deficiency; Proteins; Rats; Xanthine Oxidase

Topics: Age Factors; Animals; Ascorbic Acid; Blood Cell Count; Body Weight; Diet; Disulfiram; Female; Growth; Liver; Longevity; Male; Molybdenum; Oxygen Consumption; Rats; Reproduction; Sex Factors; Xanthine Oxidase

Topics: Adrenal Glands; Animals; Body Weight; Brain Chemistry; Calcium; Ceruloplasmin; Copper; Diet; Electron Transport Complex IV; Female; Fetus; Hemoglobinometry; Iron; Kidney; Liver; Magnesium; Maternal-Fetal Exchange; Metals; Muscles; Myocardium; Organ Size; Pregnancy; Rats; Spleen; Succinate Dehydrogenase; Thymus Gland; Xanthine Oxidase; Zinc

Topics: Allantoin; Animals; Body Weight; DNA; Feeding Behavior; Kidney; Liver; Male; Nitrogen; Organ Size; Phosphates; Protein Deficiency; Rats; RNA; Spleen; Succinate Dehydrogenase; Uric Acid; Vitamin A; Xanthine Oxidase

Topics: Allopurinol; Aminocaproates; Analgesics; Animals; Antineoplastic Agents; Azathioprine; Body Weight; Chloroquine; Colchicine; Cortisone; Cyclophosphamide; Cyproheptadine; Diazoxide; Dimethyl Sulfoxide; Encephalomyelitis, Autoimmune, Experimental; Hydrocortisone; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Methyldopa; Nialamide; Oils; Organ Size; Rats; Strychnine; Talc; Thalidomide; Thioguanine; Thiomalates

Topics: Anemia, Hypochromic; Animals; Body Weight; Duodenum; Female; Hematocrit; Hemoglobinometry; Intestinal Absorption; Intestinal Mucosa; Iron; Iron Isotopes; Kidney; Liver; Rats; Spleen; Xanthine Oxidase

Topics: Animals; Body Weight; Chickens; Diet; Dietary Proteins; Liver; Nitrogen; Organ Size; Spectrophotometry; Uric Acid; Xanthine Oxidase

Topics: Animals; Body Weight; Chickens; Dietary Proteins; Glycine max; Liver; Male; Nitrogen; Organ Size; Starvation; Time Factors; Xanthine Oxidase

Topics: Allopurinol; Athetosis; Body Height; Body Weight; Child; Child, Preschool; Chorea; Humans; Infant; Intellectual Disability; Male; Probenecid; Self Mutilation; Uric Acid; Xanthine Oxidase

Topics: Adolescent; Allopurinol; Body Height; Body Weight; Carbon Isotopes; Enzyme Therapy; Glucosephosphate Dehydrogenase Deficiency; Glycine; Gout; Hepatomegaly; Humans; Male; Probenecid; Radiochemistry; Uric Acid; Xanthine Oxidase

Several physiological and biochemical changes which occur in CD-1 pathogen-free mice during the course of infection with Listeria monocytogenes strain A4413 have been examined. Mice injected with 10(4) to 10(6) organisms by the intraperitoneal route displayed a significant depression in weight gain. In contrast, at 24 hr after infection an increment in total liver weight averaging 0.1 g was observed. The ratios of liver to body weight increased throughout the observation period. As the severity of the infection increased, food intake, as well as total liver protein and nitrogen, showed a corresponding decrease, with the diminution being most evident immediately prior to the death of the animals. Blood urea nitrogen remained relatively constant for 24 hr and then increased continuously as the infection progressed to the acute stage. Total liver lipid increased until the death of the animals. At 72 hr postinfection, a significant decrease in oxidative phosphorylation was observed. Xanthine dehydrogenase activity increased, with maximal values obtained 72 hr after infection. Uric acid levels remained constant for 24 hr, diminished at 48 hr, and then increased until the death of the animals. After 24 hr, uricase activity showed a slight increase. This activity returned to within normal ranges at 48 hr and decreased as the infection progressed to the acute stage at 72 hr. The results support the hypothesis that at least a part of the cause of death is a derangement in hepatic purine and carbohydrate metabolism. The data are also consistent with the possibility of changes in iron transport in the infected mice.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Female; Lipids; Listeria monocytogenes; Listeriosis; Liver; Mice; Organ Size; Oxidative Phosphorylation; Proteins; Urate Oxidase; Uric Acid; Xanthine Oxidase

Topics: Allantoin; Allopurinol; Animals; Body Weight; Carbon Isotopes; Carcinoma, Hepatocellular; Diet; Enzymes; Growth; Hypoxanthines; In Vitro Techniques; Kidney; Liver; Liver Neoplasms; Male; Neoplasms, Experimental; Nucleosides; Rats; Spleen; Xanthine Oxidase; Xanthines

Topics: Alcohol Oxidoreductases; Animals; Body Weight; Ethanol; Hexokinase; Liver; Male; Mice; Organ Size; Proteins; Spectrophotometry; Xanthine Oxidase

Topics: Animals; Body Weight; Dietary Proteins; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; In Vitro Techniques; Liver; Nitrogen; Nucleosides; Organ Size; Rats; Riboflavin; Subcellular Fractions; Xanthine Oxidase