allopurinol and Liver-Diseases

Allopurinol was first introduced, in 1963, as a xanthine oxidase inhibitor when it was investigated for concomitant use with cancer chemotherapy drugs. Today it is used in gout and hyperuricemia. Due to its additive benefit in preventing oxidative damage, attention has shifted towards the use of allopurinol in organ ischemia and reperfusion.. Currently, the mechanism by which allopurinol exerts a protective benefit in ischemia reperfusion related events is not fully understood. There are various theories: it may act by inhibiting the irreversible breakdown of purine substrates, and/or by inhibiting the formation of reactive oxygen species, and/or by protecting against damage to the mitochondrial membrane.. This work focuses on liver ischemia and reperfusion injury in an effort to better understand the mechanisms associated with allopurinol and with this pathological entity.. The current research, mainly in animal models, points to allopurinol having a protective benefit, particularly if used pre-ischemically in liver ischemia reperfusion injury. Furthermore, after reviewing allopurinol dosing and administration, it was found that 50 mg/kg is statistically the most effective dose in attenuating liver ischemia reperfusion injury. Owing to the limited number of samples, the time of administration did not show statistical difference, but allopurinol was often beneficial when given around 1 h before ischemia.. In conclusion, allopurinol, through its known xanthine oxidase inhibitory effect, as only one of the potential mechanisms, has demonstrated its potential application in protecting the liver during ischemia and reperfusion.

Topics: Allopurinol; Animals; Enzyme Inhibitors; Humans; Liver Diseases; Reperfusion Injury; Xanthine Oxidase

Allopurinol is an inhibitor of xanthine oxidoreductase (XOR) and inhibits the generation of uric acid (UA) as the final product of purine catabolism, as well as the resulting generation of superoxide (O2(-)), in humans. Elevation of the serum UA (SUA) level, referred to as hyperuricemia (HU), eventually leads to gout and allopurinol has been used for the treatment of HU and gout. Studies have revealed the role of elevated SUA levels and the associated oxidative stress (OS) in a broad spectrum of pathological conditions and it is anticipated that these findings would also expand the use of allopurinol as a therapeutic drug. This article presents a review of reports, mainly of recent studies, on the efficacy of allopurinol in various diseases and explores novel potential uses of the drug. Important novel and potential uses of great interest include metabolic syndrome (MetS) and related disorders, chronic kidney disease (CKD), nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Ischemia-reperfusion injury and mucositis, encountered as adverse effects of cancer treatment, have also been under investigation as potential targets for allopurinol.

Topics: Allopurinol; Enzyme Inhibitors; Fatty Liver; Humans; Liver Diseases; Metabolic Syndrome; Mucositis; Renal Insufficiency, Chronic; Reperfusion Injury; Uric Acid; Xanthine Dehydrogenase

Immunomodulator therapy with the thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of inflammatory bowel disease (IBD). Drug adverse effects and the lack of efficacy, however, commonly require withdrawal of therapy. Allopurinol, a xanthine oxidase inhibitor, was recently evaluated in its role in modifying thiopurine metabolism and improving drug efficacy in IBD.. This article reviews the role and safety of allopurinol co-therapy in the setting of thiopurine hepatotoxicity and/or non-responsiveness in IBD.. Published articles on thiopurines in the treatment of IBD were examined.. The addition of low dose allopurinol to dose-reduced thiopurine analogue seems safe but careful monitoring for adverse effects and profiling of thiopurine metabolites is essential. There is evidence of improved immunomodulator efficacy and reduced hepatotoxicity clinically but further confirmatory studies are required before more definitive treatment recommendations can be given.

Topics: Allopurinol; Azathioprine; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Diseases; Mercaptopurine

Topics: Allopurinol; Coenzymes; Diagnosis, Differential; Humans; Liver Diseases; Metalloproteins; Molybdenum Cofactors; Prognosis; Pteridines; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Ribose-Phosphate Pyrophosphokinase; Uric Acid; Xanthine

Allopurinol is a drug of wide clinical use and good tolerance. Some patients develop severe hypersensitivity due to immunologic reaction to the drug. A new case which fulfills all the diagnostic criteria of the syndrome of allopurinol hypersensitivity with associated clinical manifestations of multiple mononeuritis and evidence of granulomas and vasculitis in liver biopsy as the most significant data is reported. The syndrome was favorably resolved following withdrawal of the drug without need for corticoid therapy. The characteristics of the cases described in the Spanish literature over the last few years are globally reviewed. The absence of mortality is of note. The inconvenience of prescribing allopurinol to patients with asymptomatic hyperuricemia is emphasized.

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Granuloma; Humans; Liver Diseases; Male; Neuritis; Spain; Syndrome; Vasculitis

To review the pathophysiology, pathology, and clinical findings of allopurinol hypersensitivity syndrome (AHS), an infrequent but life-threatening adverse effect of allopurinol therapy.. A MEDLINE search (key terms hepatitis, interstitial nephritis, severe hypersensitivity, severe toxicity, vasculitis, toxic epidermal necrolysis, Lyell's syndrome, erythema multiforme, and Stevens-Johnson syndrome) was used to identify cases reported in the literature through the end of 1990.. All cases evaluated met Singer and Wallace's diagnostic criteria for AHS.. We extracted data from 101 cases of AHS reported in the literature. The following information, when available, was analyzed: (1) patient data (age, gender, medical history), (2) treatment data (daily dosage of allopurinol, duration of treatment, indications, concomitant medications, and (3) adverse-event data.. Patients were mostly middle-aged men with hypertension and/or renal failure receiving excessive doses of allopurinol primarily for asymptomatic hyperuricemia. Cutaneous rash and fever were the most common clinical findings.. Although the pathophysiologic pathway leading to the development of AHS is unknown, it probably involves an immunologic mechanism following allopurinol accumulation in patients with poor renal function. Our findings suggest that the accepted diagnostic criteria for AHS may be too broad, and we recommend the application of more restrictive criteria. There is no effective treatment for AHS. The use of allopurinol only for accepted indications and in dosages adjusted for a patient's renal function may be the only means of minimizing the incidence of AHS.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Risk Factors; Skin Diseases

Advances have recently been made in understanding the pharmacokinetics of theophylline. To correlate the new knowledge of theophylline pharmacokinetics with the drug's current status in therapy, we have critically reviewed the relevant investigations of the last 5 years. We consider data on its presumed mechanisms of action, factors affecting its clearance, its use in pregnancy, treatment of overdoses, and important drug interactions. Theophylline clearance is decreased by concomitant use of erythromycin, cimetidine, high-dose allopurinol, oral contraceptives, and caffeine. Clearance is increased by concomitant use of phenobarbital and phenytoin. Newly discovered actions of theophylline include dose-dependent improvement of diaphragmatic contractility, augmentation of ventilatory response to hypoxia, and sleep disturbances (especially with high-dose treatments). Points clinically relevant to the daily use of theophylline derivatives and the importance of sustained-release preparations are discussed. Theophylline continues to play a major role in therapy for reactive airways disease.

Topics: Acidosis; Aging; Allopurinol; Animals; Anti-Bacterial Agents; Breast Feeding; Bronchodilator Agents; Caffeine; Contraceptives, Oral; Cooking; Cystic Fibrosis; Drug Interactions; Erythromycin; Female; Heart Diseases; Histamine H2 Antagonists; Humans; Hypoxia; Infections; Kinetics; Liver Diseases; Lung Diseases, Obstructive; Maternal-Fetal Exchange; Phenobarbital; Phenytoin; Pregnancy; Respiration Disorders; Sleep; Smoking; Theophylline

Evidence is presented that supports a role of oxygen free radicals in the pathogenesis of various disorders of the digestive system. In the intestine, there is evidence that oxygen radicals play an important role in the endothelial and epithelial damage associated with certain models of ischemia. The mechanism for superoxide production in this condition differs from that described for other pathologic states (i.e., oxygen toxicity and neutrophil-mediated inflammation). This mechanism involves the reaction of xanthine oxidase, hypoxanthine, and molecular oxygen to produce a burst of oxygen radicals with reperfusion of the ischemic bowel. Evidence implicating oxygen radicals in inflammatory disorders of the digestive tract (i.e., pancreatitis), radiation injury, and hepatic cirrhosis is also presented. The available data suggest that oxygen radicals appear to be a fundamental mechanism of tissue injury in the pathogenesis of various disorders of the digestive system.

Topics: Allopurinol; Animals; Capillary Permeability; Cats; Digestive System Diseases; Dimethyl Sulfoxide; Enterocolitis, Pseudomembranous; Free Radicals; Humans; Inflammation; Intestinal Mucosa; Intestine, Small; Ischemia; Liver Diseases; Oxygen; Pancreatitis; Rats; Stomach Diseases; Superoxide Dismutase; Trypsin Inhibitors; Vascular Resistance; Xanthine Oxidase

Topics: Amino Acid Sequence; Apoferritins; Electrophoresis; Female; Ferritins; Hemochromatosis; Hodgkin Disease; Humans; Iron; Leukemia; Liver; Liver Diseases; Male; Molecular Conformation; Molecular Weight; Oxidoreductases; Xanthine Oxidase

To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once-daily 80-mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.

Topics: Administration, Oral; Adult; Biotransformation; Drug Administration Schedule; Enzyme Inhibitors; Febuxostat; Female; Humans; Liver Diseases; Male; Middle Aged; Thiazoles; Xanthine Oxidase

Topics: Acute Kidney Injury; Alanine Transaminase; Animals; Aspartate Aminotransferases; Cecum; Creatinine; Febuxostat; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Kidney; Ligation; Liver; Liver Diseases; Male; Protective Agents; Rats, Wistar; Sepsis; Urea; Xanthine Oxidase

There is controversy as to whether hyperuricemia is an independent risk factor for cardiometabolic diseases. The serum level of uric acid is affected by a wide variety of factors involved in its production and excretion. In contrast, evidence has accumulated that locally- and systemically-activated xanthine oxidase (XO), a rate-limiting enzyme for production of uric acid, is linked to metabolic derangement in humans and rodents. We therefore explored the clinical implication of plasma XO activity in patients with type 2 diabetes mellitus and metabolic syndrome (MetS).. We enrolled 60 patients with type 2 diabetes mellitus and MetS. MetS was defined according to the 2005 International Diabetes Federation guidelines. Plasma XO activity was measured by highly-sensitive fluorometric assay measuring the conversion of pterin to isoxanthopterin, and explored associations between the value of plasma XO activity and metabolic parameters.. The value of plasma XO activity was correlated with indices of insulin resistance and the level of circulating liver transaminases. In contrast, the level of serum uric acid was not correlated with indices of insulin resistance. The value of plasma XO activity was not correlated with the serum uric acid level.. Plasma XO activity correlates with indices of insulin resistance and liver dysfunction in Japanese patients with type 2 diabetes mellitus and MetS. Through assessing the plasma XO activity, patients showing normal levels of serum uric acid with higher activity of XO can be screened, thereby possibly providing a clue to uncovering metabolic risks in type 2 diabetes mellitus and MetS patients.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Liver Diseases; Male; Metabolic Syndrome; Middle Aged; Pilot Projects; Risk Factors; Xanthine Oxidase; Young Adult

We aimed to evaluate whether two methionine-related compounds, S-adenosylmethionine (SAM), and selenomethionine (SM), could lessen liver damage induced by regurgitated bile in a model of rat bile duct ligation (BDL). Hepatoprotective potentials of S-adenosylmethionine and selenomethionine were estimated based on the changes of serum liver damage parameters (aminotransferases, alkaline phosphatase, gamma-glutamyltranspeptidase and lactate dehydrogenase activity, and bilirubin concentration), tissue oxidative [xanthine oxidase (XO) and catalase activity, thiobarbituric acid reactive substances (TBARS) levels] and inflammatory [tumor necrosis factor-alfa (TNF-α) concentration] parameters, and morphological liver tissue alterations that follow cholestasis. The treatment regimens proved themselves able to prevent significant liver damage induced by cholestasis. Both SAM and SM decreased XO activity and TBARS levels and increased catalase activity, while only SM significantly reduced TNF-α concentration. Morphological changes related to bile-induced liver damage were also found to be partially diminished by SAM and SM. In view of the mechanisms of action of the two tested methionine-derived compounds, one might say that SM predominantly acted as an antioxidant, while SAM exerted its activity by potentially modulating different gene expression and protein structures. It is also worth mentioning that this is the first study (to the best of our knowledge) that dealt with the effects of SM on BDL-induced liver injury in rats and of the findings that speak favorably of this powerful antioxidant.

Topics: Animals; Catalase; Cholestasis; Liver Diseases; Male; Rats; Rats, Wistar; S-Adenosylmethionine; Selenomethionine; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

An epidemic of chronic kidney disease (CKD) has been observed in Central America among workers in the sugarcane fields. One hypothesis is that the CKD may be caused by recurrent heat stress and dehydration, and potentially by hyperuricemia. Accordingly, we developed a murine model of kidney injury associated with recurrent heat stress. In the current experiment, we tested whether treatment with allopurinol (a xanthine oxidase inhibitor that reduces serum urate) provides renal protection against recurrent heat stress and dehydration. Eight-week-old male C57BL/6 mice were subjected to recurrent heat stress (39.5°C for 30 min, 7 times daily, for 5 wk) with or without allopurinol treatment and were compared with control animals with or without allopurinol treatment. Mice were allowed ad libitum access to normal laboratory chow (Harlan Teklad). Kidney histology, liver histology, and renal function were examined. Heat stress conferred both kidney and liver injury. Kidneys showed loss of proximal tubules, infiltration of monocyte/macrophages, and interstitial collagen deposition, while livers of heat-stressed mice displayed an increase in macrophages, collagen deposition, and myofibroblasts. Allopurinol provided significant protection and improved renal function in the heat-stressed mice. The renal protection was associated with reduction in intrarenal uric acid concentration and heat shock protein 70 expression. Heat stress-induced renal and liver injury can be protected with allopurinol treatment. We recommend a clinical trial of allopurinol for individuals developing renal injury in rural areas of Central America where the epidemic of chronic kidney disease is occurring.

Topics: Allopurinol; Animals; Collagen; Disease Models, Animal; Enzyme Inhibitors; Heat Stress Disorders; Hot Temperature; HSP70 Heat-Shock Proteins; Hyperthermia, Induced; Kidney; Kidney Diseases; Liver; Liver Diseases; Male; Mice, Inbred C57BL; Uric Acid; Xanthine Oxidase

We aimed to clarify if melatonin treatment (2 mg/kg i.p.) may favorably impact the liver tissue in rats exposed to microwave radiation. The experiment was performed on 84 six-weeks-old Wistar male rats exposed for 4h a day, for 20, 40 and 60 days, respectively, to microwaves (900 MHz, 100-300 microT, 54-160 V/m). Rats were divided in to four groups: I (control) - rats treated with saline, II (Mel) - rats treated with melatonin, III (MWs) - microwave exposed rats, IV (MWs + Mel) - MWs exposed rats treated with melatonin. We evaluated oxidative stress parameters (malondialdehyde and carbonyl group content), catalase, xanthine oxidase, deoxyribonuclease I and II activity.. Oxidative stress is the key mechanism of the microwave induced tissue injury. Melatonin, a lipophilic indoleamine primarily synthesized and released from the pineal gland is a powerful antioxidant.. Exposure to microwaves caused an increase in malondialdehyde after 40 (p < 0.01), protein carbonyl content after 20 (p < 0.05), catalase (p < 0.05) and xantine oxidase activity (p < 0.05) after 40 days. Increase in deoxyribonuclease I activity was observed after 60 days (p < 0.05), while deoxyribonuclease II activity was unaffected. Melatonin treatment led to malondialdehyde decrease after 40 days (p< 0.05), but surprisingly had no effect on other analyzed parameters.. Melatonin exerts certain antioxidant effects in the liver of rats exposed to microwaves, by diminishing the intensity of lipid peroxidation(Fig. 6, Ref. 32).

Topics: Animals; Antioxidants; Catalase; Dose-Response Relationship, Radiation; Lipid Peroxidation; Liver Diseases; Male; Malondialdehyde; Melatonin; Microwaves; Oxidative Stress; Radiation Injuries, Experimental; Rats; Rats, Wistar; Reactive Oxygen Species; Xanthine Oxidase

This study investigated iron-induced injury after warm ischemia in a non-heart-beating (NHB) rat liver model and the effects of deferoxamine (DFO). Livers from heart-beating (HB) rats or rats that were NHB for 60 minutes were stored in University of Wisconsin solution for 5 hours at 4°C [cold storage (CS)] and then were subjected to 2 hours of machine reperfusion (MRP) at 37°C. Three NHB groups were compared: (1) no DFO, (2) DFO 30 minutes before cardiac arrest and during CS and MRP, and (3) DFO during CS and MRP. Aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in the NHB perfusate were significantly elevated (P < 0.01) in comparison with levels in HB controls after CS and MRP. After CS, the levels of iron and tumor necrosis factor α (TNF-α) were 0.077 ± 0.007 μmol/g and 151 ± 26 pg/g, respectively, in the NHB group and 0.022 ± 0.004 μmol/g and 17 ± 7 pg/g, respectively, in the HB group (P < 0.01). After MRP, LDH significantly correlated with iron (R(2)  = 0.81, P < 0.01). The DFO pretreatment of NHB donors decreased AST (7.3 ± 0.8 versus 4.0 ± 0.5 U/g of liver, P < 0.05) and LDH (42.5 ± 4.1 versus 20.4 ± 2.5 U/g of liver, P < 0.05) with 2 hours of MRP and increased bile flow during MRP (142 ± 34 versus 240 ± 18 μL/g, P < 0.05). It also reduced the levels of iron (0.077 ± 0.007 versus 0.050 ± 0.008 μmol/g, P < 0.05) and TNF-α (151 ± 26 versus 51 ± 13 pg/g, P < 0.05) after CS and the levels of lipid peroxidation products F2-isoprostane (149 ± 11 versus 99 ± 10 ng/g, P < 0.05) and malondialdehyde (1.58 ± 0.1 versus 1.14 ± 0.08 μmol/g, P < 0.05) after MRP. In conclusion, iron-initiated oxidative stress is likely involved in NHB donor liver injury, and importantly, DFO pretreatment reduces liver damage.

Topics: Adenosine; Allopurinol; Animals; Aspartate Aminotransferases; Bile; Deferoxamine; Disease Models, Animal; F2-Isoprostanes; Glutathione; Heart Arrest; Insulin; Iron; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Malondialdehyde; Organ Preservation Solutions; Oxidative Stress; Perfusion; Raffinose; Rats; Tumor Necrosis Factor-alpha; Warm Ischemia

S-Nitrosated human serum albumin (SNO-HSA) is useful in preventing liver ischemia/reperfusion injury, and SNO-HSA should thus be able to prevent cell injury during liver transplantation. However, the potential protective effect of SNO-HSA on a combination of cold and warm ischemia, which is obligatory when performing liver transplantation, has not been examined. Therefore, we evaluated the protective effect of SNO-HSA added to University of Wisconsin (UW) solution during cold or/and warm ischemia in situ and in vitro. First, we observed that apoptotic and necrotic cell death were increased during cold and warm ischemia, respectively. SNO-HSA, which possesses anti-apoptosis activity at low NO concentrations, can inhibit cold ischemia injury both in situ and in vitro. In contrast, SNO-HSA had no significant effect on warm liver ischemia injury which, however, can be reduced by UW solution. We also demonstrated that the cellular uptake of NO from SNO-HSA can occur during cold ischemia resulting in induction of heme oxygenase-1 within 3h of cold ischemia. Our results indicate that treatment with SNO-HSA or UW solution alone is not sufficient to inhibit liver injury during a period of both cold and warm ischemia. However, a combination of SNO-HSA and UW solution can be used to prevent the two types of ischemia. SNO-HSA-added UW solution could be very useful in transplantation, because the previously imposed constraints on preservation time can be removed. This is a great advantage in a situation as the present one with increased utilization of scarce donor organs for more recipients.

Topics: Adenosine; Allopurinol; Analysis of Variance; Animals; Apoptosis; Glutathione; Hep G2 Cells; Humans; Insulin; Liver; Liver Diseases; Liver Transplantation; Male; Necrosis; Nitric Oxide Donors; Nitroso Compounds; Organ Preservation Solutions; Raffinose; Rats; Rats, Wistar; Reperfusion Injury; Serum Albumin; Serum Albumin, Human

In this work, we evaluated the effects of allopurinol (ALO), an inhibitor of xanthine oxidase (XO), on hepatic lesions caused by ischemia/reperfusion (I/R) in the rabbit liver. Rabbits were pretreated with ALO (10 mg/kg IV) or saline solution 0.9% before the hepatic I/R procedure. The effects of ALO on hepatic injury were evaluated before and after I/R. A standard, warm hepatic I/R procedure caused profound acute liver injury, as indicated by elevated serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, as well as a high apoptotic cell count. All of these changes were reversed by the administration of ALO before the hepatic I/R procedure. In conclusion, ALO exerted protective effects on hepatic I/R lesions. This protective effect of ALO was probably associated with blocking the generation of superoxide anions during the hepatic I/R procedure by inhibiting XO activity.

Topics: Alanine Transaminase; Allopurinol; Animals; Aspartate Aminotransferases; Enzyme Inhibitors; L-Lactate Dehydrogenase; Liver Diseases; Male; Rabbits; Reperfusion Injury; Xanthine Oxidase

Oxidative stress may have a role in liver damage after acute renal injury due to various reasons such as ischemia reperfusion (IR). Diabetes mellitus (DM) is an important disease for kidneys and may cause nephropathy as a long term complication. The aim of this study was to investigate protective effect of melatonin, a potent antioxidant, against distant organ injury on liver induced by renal IR in rats with or without DM. The rats were divided into six groups: control (n=7), DM (n=5), IR (n=7), DM+IR (n=7), melatonin+IR (Mel+IR) (melatonin, 4 mg/ kg during 15 days) (n=7), and Mel+DM+IR groups (n=7). Diabetes developed 3 days after single i.p. dose of 45 mg/kg streptozotocin. After 15 day, the left renal artery was occluded for 30 min followed 24 h of reperfusion in IR performed groups. DM did not alter oxidative parameters alone in liver tissue. The levels of malondialdehyde, protein carbonyl and nitric oxide with activities of xanthine oxidase and myeloperoxidase were increased in liver tissues of diabetic and non-diabetic IR groups. Nitric oxide level in DM was higher than control. The activities of catalase and superoxide dismutase were increased in IR groups in comparison with control and DM. ALT and AST levels were higher in IR and DM+IR groups than control and DM. Melatonin treatment reversed all these oxidant and antioxidant parameters to control values as well as serum liver enzymes. We concluded that renal IR may affect distant organs such as liver and oxidative stress may play role on this injury, but DM has not an effect on kidney induced distant organ injury via oxidant stress. Also, it was concluded that melatonin treatment may prevent liver oxidant stress induced by distant injury of kidney IR.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Catalase; Diabetes Mellitus, Experimental; Kidney; Liver; Liver Diseases; Male; Malondialdehyde; Melatonin; Nitric Oxide; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Xanthine Oxidase

Oxidative stress occurs in remote liver injury, but the origin of the oxidant generation has yet to be thoroughly delineated. Some reports suggest that the source of the distant oxidative stress originates from the site of initial insult [i.e., xanthine oxidase (XO)]; however, it could also be derived from sources such as phagocytic and/or vascular NAD(P)H oxidase (Nox) enzymes. With a murine model of bilateral hindlimb ischemia-reperfusion, we describe here a mechanism for Nox-dependent oxidant production that contributes, at least in part, to remote hepatic parenchymal injury and sinusoidal endothelial cell (SEC) dysfunction. To determine whether Nox enzymes were the source of oxidants, mice were treated immediately after the onset of hindlimb ischemia with specific inhibitors to XO (50 mg/kg ip allopurinol) or Nox (10 mg/kg ip gp91ds-tat and 3 mg/kg ip apocynin). After 1 h of ischemia, hindlimbs were reperfused for either 3 or 6 h. Inhibition of XO failed to provide any improvement in parenchymal injury, SEC dysfunction, neutrophil accumulation, or microvascular dysfunction. In contrast, the inhibition of Nox enzymes prevented the progression (6 h) of parenchymal injury, significantly protected against SEC dysfunction, and completely prevented signs of neutrophil-derived oxidant stress. At the same time, however, inhibition of Nox failed to protect against the early parenchymal injury and microvascular dysfunction at 3 h of reperfusion. These data confirm that microvascular perfusion deficits are not essential for the pathogenesis of remote hepatic parenchymal injury. The data also suggest that Nox enzymes, not XO, are involved in the progression of compromised hepatic parenchymal and endothelial integrity during a systemic inflammatory response.

Topics: Animals; Disease Progression; Endothelium; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Microcirculation; Models, Biological; NADPH Oxidases; Neutrophils; Oxidative Stress; Peroxidase; Reperfusion Injury; Tyrosine; Xanthine Oxidase

Acute iron intoxication from the accidental ingestion of iron-containing preparations is one important cause of death in children. The aim of this study was to investigate the protective effect of sesame oil on acute iron-induced lipid peroxidation (LPO) and hepatic injury in mice. Acute iron intoxication was induced by giving ferric nitrilotriacetate to mice. Hepatic function was assessed using blood biochemistry. Free radicals were determined using a high-performance chemiluminescence analyzer. Ferric nitrilotriacetate increased serum ferrous (Fe) and LPO levels, and induced acute hepatic injury. Sesame oil (a) dose-dependently decreased acute iron-induced LPO and hepatic injury, (b) reduced acute iron-associated hydroxyl radical and superoxide anion generation, and (c) inhibited the activity of xanthine oxidase in acute iron intoxication. Thus, sesame oil might ameliorate LPO and acute hepatic injury by inhibiting xanthine oxidase-initiated superoxide anion generation, thereby reducing hydroxyl radical production, at least partially, in acutely iron-intoxicated mice.

Topics: Animals; Hydroxyl Radical; Iron; Lipid Peroxidation; Liver; Liver Diseases; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Sesame Oil; Superoxides; Xanthine Oxidase

For cadaveric transplantations, histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solutions have been shown to engender similar outcomes. In September 2004, our institution changed from UW to HTK as the primary preservation solution for liver and kidney transplantations. We reviewed records of living-donor liver transplant recipients from September 2001 to December 2005. This study compared early postoperative outcomes of liver transplantation using the 2 solutions. Perfusion was performed first via the portal vein and then via the hepatic artery until the outflow became clear. Patients were compared based on the organ preservation solution. The analysis included patient demographics, early postoperative complication rates, mortality rates, number of acute rejection episodes, costs for preservation solutions, and results of 1-, 7-, 14-, and 30- day liver function tests. Patients in both groups were managed with similar operative techniques, immunosuppressive regimens, and donor liver criteria. Statistical analyses were performed with chi- square and Mann-Whitney U tests. Donor and patient demographics were similar. No statistically significant differences were observed between the groups with regard to posttransplantation liver biochemistry, complication rates, number of acute rejection episodes, and mortality rates. The mean infused volume of preservation solution was 1000 +/- 400 mL (range, 500-2000 mL) for all patients. These volumes corresponded to a cost savings of US 148 dollars/L when using HTK solution. In conclusion, UW and HTK were equally effective and safe for perfusion of living-donor liver grafts; however, the use of HTK solution provided significant cost savings.

Topics: Adenosine; Adult; Allopurinol; Female; Glucose; Glutathione; Humans; Immunosuppressive Agents; Insulin; Liver; Liver Diseases; Liver Transplantation; Living Donors; Male; Mannitol; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Retrospective Studies; Tacrolimus

Although hypothermic machine perfusion (HMP) preservation has been shown to improve organ function and to expand the organ donor pool, problems still exist with the current HMP technology for liver preservation. The present study was conducted to investigate endothelial and hepatocellular functions following extended HMP (> r =24 hr) in rat liver model.. Following 24-hour hypothermic HMP with University of Wisconsin (UW) solution or 24-hour simple cold storage (SCS), livers were reperfused with Krebs-Henseleit buffer solution at 37 degree C for 30 minutes. Hepatocyte damage and function were assessed by measuring lactate dehydrogenase (LDH) activity, bile production, and indocyanine green (ICG) extraction. Sinusoidal endothelial cell (SEC) function and permeability were determined by hyaluronic acid (HA) uptake and multiple indicator dilution (MID) method, respectively.. After 24-hour hypothermic preservation, HMP livers showed lower released LDH levels, higher bile flow rate, and greater hepatic ICG uptake compared with SCS livers. However, LDH levels became significantly higher in HMP than in SCS after 30 minutes of warm perfusion. The increased enzyme levels were accompanied by a significant increase in endothelial permeability to albumin and a decrease in hyaluronic acid uptake in HMP compared to SCS. Liver wet/dry weight ratio confirmed a greater edema in HMP livers than SCS livers.. These results suggest that 24-hour hypothermic HMP may help preservation of hepatocyte function, but endothelial cell dysfunction during the cold preservation may play a key role in hepatocyte dysfunction and parenchymal cell death upon reperfusion.

Topics: Adenosine; Albumins; Allopurinol; Animals; Bile; Cryopreservation; Edema; Endothelium; Glucose; Glutathione; Hepatocytes; Hyaluronic Acid; Insulin; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Organ Preservation; Organ Preservation Solutions; Perfusion; Permeability; Raffinose; Rats; Rats, Sprague-Dawley; Time Factors; Tromethamine

Xanthine oxidoreductase (XOR) is a widely distributed enzyme, involved in the metabolism of purines, which generates superoxide and is thought to be involved in free radical-generated tissue injury. It is present at high concentrations in the liver, from where it may be released during liver injury into the circulation, binding to vascular endothelium and causing vascular dysfunction. The cellular localization of the enzyme, essential to understanding its function, is, however, still debated. The present study has used a highly specific mouse monoclonal antibody to define the cellular distribution of XOR in normal and cirrhotic human liver. As shown previously, XOR is present in hepatocytes. However, the novel finding of this study is that XOR is present in bile duct epithelial cells, where it is concentrated toward the luminal surface. Moreover, in liver disease, proliferating bile ducts are also strongly positive for XOR. These findings suggest that the enzyme is secreted into bile, and this was confirmed by analysis of human and rat bile. Xanthine oxidase activity was 10 to 20-fold higher in liver tissue obtained from patients with liver disease, than in healthy liver. We conclude that XOR is expressed primarily in hepatocytes, but is also present in bile duct epithelial cells and is secreted into bile. Its role in bile is unknown but it may be involved in innate immunity of the bowel muscosa.

Topics: Animals; Antibodies, Monoclonal; Bile; Bile Ducts; Blotting, Western; Cell Polarity; Cholangitis, Sclerosing; Electrophoresis, Polyacrylamide Gel; Epithelial Cells; Hepatitis C; Hepatocytes; Humans; Hyperoxaluria, Primary; Immunoenzyme Techniques; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Diseases; Liver Diseases, Alcoholic; Mice; Mice, Inbred BALB C; Microscopy, Confocal; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Ischemic-type biliary lesions (ITBLs) lead to considerable morbidity after orthotopic liver transplantation (OLT). The exact pathogenesis is unknown. We tested the hypothesis that insufficient perfusion of biliary arterial vessels might be responsible for ITBLs. This could be prevented by improved perfusion techniques. Since February 2000, we performed a controlled study using arterial back-table pressure perfusion (AP) to achieve reliable perfusion of the biliary-tract capillary system, which may be impaired by the high viscosity of University of Wisconsin solution. We retrospectively analyzed 190 OLTs performed between September 1997 and July 2002 with regard to ITBLs. One hundred thirty-one grafts were preserved by in situ standard perfusion (SP), including portal perfusion, whereas in 59 cases, additional AP was performed. Donor-related factors, recipient age, indication for OLT, OLT technique, immunosuppression, and ischemia time were similar in both groups. In the SP group, 21 of 131 patients (16%) developed ITBLs. Only 1 of 59 patients with grafts receiving AP developed ITBLs. This difference was highly significant (P =.004). Peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels within the first 3 days were significantly lower in the AP group (AST, P =.016; ALT, P =.007). Multivariate analysis showed a significant influence of AP (P =.010) and donor age (P =.003) on the development of ITBLs. AP is an easy and reliable method to prevent ITBLs in OLT. It therefore should be used as the standard technique in liver procurement.

Topics: Adenosine; Adult; Aged; Allopurinol; Bile Ducts; Glutathione; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Liver Diseases; Liver Transplantation; Middle Aged; Organ Preservation Solutions; Perfusion; Postoperative Complications; Pressure; Raffinose; Reperfusion Injury; Retrospective Studies; Survival Rate; Viscosity

Donor cells can be preserved in University of Wisconsin (UW), histidine-tryptophan-ketoglutarate (HTK), or Celsior solution. However, differences in efficacy and mode of action in preventing hypothermia-induced cell injury have not been unequivocally clarified. Therefore, we investigated and compared necrotic and apoptotic cell death of freshly isolated primary porcine hepatocytes after hypothermic preservation in UW, HTK, and Celsior solutions and subsequent normothermic culturing. Hepatocytes were isolated from porcine livers, divided in fractions, and hypothermically (4 degrees C) stored in phosphate-buffered saline (PBS), UW, HTK, or Celsior solution. Cell necrosis and apoptosis were assessed after 24- and 48-h hypothermic storage and after 24-h normothermic culturing following the hypothermic preservation periods. Necrosis was assessed by trypan blue exclusion, lactate dehydrogenase (LDH) release, and mitochondrial 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction. Apoptosis was assessed by the induction of histone-associated DNA fragments and cellular caspase-3 activity. Trypan blue exclusion, LDH release, and MTT reduction of hypothermically preserved hepatocytes showed a decrease in cell viability of more than 50% during the first 24 h of hypothermic preservation. Cell viability was further decreased after 48-h preservation. DNA fragmentation was slightly enhanced in hepatocytes after preservation in all solutions, but caspase-3 activity was not significantly increased in these cells. Normothermic culturing of hypothermically preserved cells further decreased cell viability as assessed by LDH release and MTT reduction. Normothermic culturing of hypothermically preserved hepatocytes induced DNA fragmentation, but caspase-3 activity was not hanced in these cells. Trypan blue exclusion, LDH leakage, and MTT reduction demonstrated the highest cell viability after storage in Celsior, and DNA fragmentation was the lowest in cells that had been stored in PBS and UW solutions. None of the preservation solutions tested in this study was capable of adequately preventing cell death of isolated porcine hepatocytes after 24-h hypothermic preservation and subsequent 24-h normothermic culturing. Culturing of isolated and hypothermically preserved hepatocytes induces DNA fragmentation, but does not lead to caspase-3 activation. With respect to necrosis and DNA fragmentation of hypothermically preserved cells, UW and Celsior were superio

Topics: Adenosine; Allopurinol; Animals; Apoptosis; Caspase 3; Caspases; Cell Count; Cell Culture Techniques; Cell Division; Cell Survival; Cells, Cultured; Cryopreservation; Cryoprotective Agents; Disaccharides; DNA Fragmentation; Electrolytes; Female; Glucose; Glutamates; Glutathione; Hepatocytes; Histidine; Hypothermia, Induced; Insulin; L-Lactate Dehydrogenase; Liver Diseases; Male; Mannitol; Models, Biological; Necrosis; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Tetrazolium Salts; Thiazoles; Tissue Transplantation

To clarify the relationship between plasma antioxidant activity and diseases in dogs, plasma samples were collected from 6 healthy dogs and 16 diseased dogs (6 dogs with cancer, 5 dogs with hepatic disease, and 5 dogs with inflammation ), and measured superoxide anion scavenging activities. Antioxidant activities of canine plasma were evaluated by measuring their superoxide anion (O(2)(-.)) scavenging activities with electron spin response spectroscopy combined with spin trapping reagent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Total O(2)(-.) scavenging activities in the presence of plasma of diseased dogs tended to be higher than those in healthy controls, especially significant higher activities in the presence of canine plasma of hepatic disease and inflammation were observed. In diseased dogs, KCN-insensitive activities, suggesting the activity of manganese-containing superoxide dismutase (Mn-SOD), were significantly higher than those in healthy controls. Therefore, it seems that there is a possibility of utilizing of plasma O(2)(-.) scavenging activity as one of clinical indicators for oxidative-related diseases such as cancer, hepatic disease and inflammation in dogs.

Topics: Animals; Case-Control Studies; Cyclic N-Oxides; Dog Diseases; Dogs; Electron Spin Resonance Spectroscopy; Female; Free Radical Scavengers; Hypoxanthine; Inflammation; Liver Diseases; Male; Neoplasms; Spin Labels; Superoxides; Xanthine Oxidase

Normal human hepatocytes are an ideal source of liver-targeted cell therapies, such as hepatocyte transplantation and bioartificial livers, but availability of human donor livers for liver cell isolation is severely limited. To effectively utilize scarce donor organs for cell therapies, it is of extreme importance to establish an efficient isolation technique and an effective cold preservation solution for transportation of isolated cells. A lateral segment of the liver was surgically resected from pigs weighing 10 kg and a four-step collagenase and dispase digestion was conducted. Isolated hepatocytes were subjected to 8-h cold storage on ice. The following preservation solutions were tested: 1) University of Wisconsin (UW) solution, 2) UW with 100 microg/ml of ascorbic acid-2 glucoside (AA2G), 3) 100% fetal bovine serum (FBS), and 4) Dulbecco's modified Eagle's medium (DMEM) supplemented with 100% FBS. The mean viability of porcine hepatocytes was 95.5 +/- 2.5% when isolated in three independent experiments. Viability, plating efficiency, membrane stability, and ammonia metabolic capacity of cold-preserved hepatocytes were significantly better maintained by the use of UW solution. When AA2G (100 microg/ml) was combined with UW solution, such parameters were further improved. It was explained by inhibition of caspase-3 activation and retention of ATP at high levels of hepatocytes preserved with UW solution containing AA2G. The present work demonstrates that a combination of UW solution with AA2G (100 microg/ml) would be a useful cold preservation means for the development of cell therapies.

Topics: Adenosine; Adenosine Triphosphate; Allopurinol; Ammonia; Animals; Apoptosis; Ascorbic Acid; Caspase 3; Caspase Inhibitors; Caspases; Cell Culture Techniques; Cell Membrane; Cell Separation; Cell Survival; Cell Transplantation; Cells, Cultured; Cryopreservation; Cryoprotective Agents; Glutathione; Hepatocytes; Insulin; Liver Diseases; Liver Transplantation; Male; Organ Preservation Solutions; Raffinose; Sus scrofa; Transplantation, Heterologous

Development of liver-targeted cell therapies, such as hepatocyte transplantation and bioartificial livers, requires a large amount of functional hepatocytes as needed. To achieve this development, establishing an excellent cryopreservation method of hepatocytes is an extremely important issue. Therefore, we performed a comparative review of cryoprotective effects of various cryopreservation solutions using primarily isolated porcine hepatocytes. Porcine hepatocytes were isolated with a four-step dispase and collagenase perfusion method. The obtained hepatocytes with the initial viabilities of 76%, 84%, and 96% were assigned to the following four groups for cryopreservation at -80 degrees C: Dulbecco's modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS) + 12% dimethyl sulfoxide (DMSO) (group A), University of Wisconsin (UW) solution + 12% DMSO (group B), Cell Banker 1 (group C), and Cell Banker 2 (group D). The hepatocytes in each group were thawed at 3 days, 10 days, and 5 months of cryopreservation and subjected to comparative analyses, including viability, plating efficiency, LDH release, ammonia removal test, and lentiviral gene transfer. These parameters were the most favorable in the hepatocytes cryopreserved with UW solution. Approximately 5% of thawed cryopreserved porcine hepatocytes expressed LacZ activity after lentiviral transduction. Intrasplenic transplantation of UW solution-cryopreserved hepatocytes improved the survival of rats treated with D-galactosamine. UW solution maintained the functions of cryopreserved porcine hepatocytes.

Topics: Adenosine; Allopurinol; Ammonia; Animals; Cell Culture Techniques; Cell Separation; Cell Survival; Cell Transplantation; Cryopreservation; Cryoprotective Agents; Genetic Vectors; Glutathione; Hepatocytes; Insulin; L-Lactate Dehydrogenase; Lac Operon; Liver Diseases; Liver Transplantation; Male; Organ Preservation Solutions; Raffinose; Rats; Rats, Wistar; Sus scrofa; Transduction, Genetic; Transplantation, Heterologous

Extensive and severe hepatic centrilobular hemorrhagic necrosis is a common finding in hepatic vein obstruction and Budd-Chiari syndrome. Some drugs, including allopurinol, can also cause this histopathologic appearance but to our knowledge in this setting the lesions are not so massive. Here we report a case of a 41-year-old female who developed fever, pruritic skin rash, jaundice, eosinophilia, abnormal liver function tests, and acute renal failure 3 weeks after the beginning of allopurinol treatment, complicated with severe hepatocyte necrosis around most terminal hepatic venules suggesting Budd-Chiari syndrome.

Topics: Acute Kidney Injury; Adult; Allopurinol; Antihypertensive Agents; Chemical and Drug Induced Liver Injury; Female; Hemorrhage; Humans; Hypertension; Liver Diseases; Necrosis

Hepatocellular transplant may potentially be efficacious for the treatment of selected liver metabolic disorders and acute hepatic failure. On the other hand, the use of hepatocyte cold preservation techniques in these transplantation protocols would allow to have available cells at the right time and place and, consequently, make an optimal use of scarce human hepatocytes. In our experiments we evaluated the biodistribution and functionality of cold preserved hepatocytes transplanted in the spleen of syngeneic rats. Isolated hepatocytes were labeled with the fluorescent dye 5(6)-carboxyfluorescein diacetate succinimidyl-ester, cold-preserved in modified University of Wisconsin (UW) solution for 48 or 96 h, and then transplanted into the spleen. Recipient animals were euthanized at 0 and 3 h, and at 1, 2, 3, 5, 10, and 14 days after transplantation for tissue analysis. Labeled hepatocytes were clearly identifiable in the recipient tissues up to 14 days later. Fluorescence microscopy also showed no significant differences in biodistribution when either cold stored or freshly isolated hepatocytes were transplanted. In addition, functional activity of transplanted cells was demonstrated by immunohistochemical detection of albumin at levels comparable to those found in normal hepatocytes. Our findings establish that cold preserved hepatocytes appear morphologically and biochemically normal after intrasplenic transplantation. Consequently, it indicates that modified UW solution makes it possible to safety preserve hepatocytes for up to 96 h before transplantation, perhaps providing sufficient time for hepatocyte allocation and potential recipient preparation, if applicable clinically.

Topics: Adenosine; Albumins; Allopurinol; Animals; Cryopreservation; Fluoresceins; Fluorescent Dyes; Glutathione; Graft Survival; Hepatocytes; Immunohistochemistry; Insulin; Liver Diseases; Male; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Wistar; Spleen; Succinimides; Tissue Transplantation

1. Although oral administration of 400 mg/kg acetaminophen (APAP) or 1.8-3.4 g/kg sucrose had no effect on serum levels of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH), their co-administration resulted in 20-fold increases in ALT/SDH activities. APAP alone (1250 mg/kg, p.o.) caused the elevation hepatotoxicity parameters, but the levels were lower than observed with co-administration of APAP (400 mg/kg) and sucrose (2.6 or 3.4 g/kg). 2. Sucrose-associated increase in serum ALT/SDH activities was selective with APAP and not detected with carbon tetrachloride (160 mg/kg, i.p.), D-galactosamine (400 mg/kg, i.p.) or alpha-naphthyl isothiocyanate (100 mg/kg, p.o.). 3. To verify the synergistic mechanism of sucrose, a major reactive intermediate of APAP, N-acetyl-p-benzoquinone imine (NAPQI), was given via the portal vein to rat pretreated with sucrose. Clear elevation of ALT/SDH activities was detected in the co-treated group. These results, together with an allopurinol-inhibition experiment, suggest the involvement of high-dose sucrose at a step(s) occurring after the metabolic activation of APAP. 4. Co-administration of glucose or fructose as well as sucrose elevated APAP-induced hepatotoxicity parameters in rat. Fructose but not glucose elevated APAP- or NAPQI-induced LDH leakage in a primary hepatocyte system. The results suggest the primary role of fructose is on the sucrose enhancement of APAP toxicity in rat.

Topics: Acetaminophen; Alanine Transaminase; Allopurinol; Animals; Benzoquinones; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Drug Synergism; Enzyme Inhibitors; Fructose; Glucose; Imines; L-Iditol 2-Dehydrogenase; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Portal Vein; Rats; Rats, Sprague-Dawley; Sucrose; Xanthine Oxidase

Xanthine oxidase was purified from human milk and used to immunise rabbits. A competitive immunoenzymatic assay with purified enzyme and rabbit antiserum was optimised to measure xanthine oxidase in human serum, the lowest detectable amount being 0.03 pmol of enzymatic protein. Thus, the test (i) is sensitive enough to determine xanthine oxidase in human serum, being more sensitive than the spectrophotometric method, (ii) it is more convenient for clinical laboratories than other sensitive tests and (iii) it has the advantage over the enzyme activity-based assays of also detecting inactive enzyme molecules. A competitive enzyme-linked immunosorbent assay (ELISA) was used to measure the serum xanthine oxidase level in healthy donors and in patients with liver diseases, and it was found that any concentration below 1 mg/L is in the normal range.

Topics: Animals; Antibody Specificity; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Humans; Immune Sera; Liver Diseases; Milk; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Brain Death; Glutathione; Humans; Insulin; Liver Diseases; Liver Transplantation; Multivariate Analysis; Organ Preservation; Organ Preservation Solutions; Postoperative Complications; Raffinose; Risk Factors; Tissue Donors

Oxidant stress has been implicated as playing a role in the pathogenesis of cholestatic liver injury. The objective of this study was to determine whether the xanthine oxidase/xanthine dehydrogenase enzyme system was involved in this oxidant stress. Adult Sprague-Dawley rats were treated with the xanthine oxidase inhibitor, oxypurinol, and randomized to bile duct ligation or sham surgery; vehicle-treated, sham-operated rats served as controls. After 5 d of bile duct ligation, serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin concentrations were significantly elevated, and increased lipid peroxidation of hepatic mitochondria and microsomes was present. Treatment with oxypurinol reduced the aspartate aminotransferase, alanine aminotransferase, and bilirubin values by 26-47% but did not alter the increased lipid peroxidation of mitochondria and microsomes. Serum vitamin E:total lipids ratio was also reduced in both bile duct-ligated groups, consistent with oxidant injury. These data show that inhibition of xanthine oxidase reduces biochemical evidence of hepatocellular injury during bile duct ligation without affecting oxidant damage to intracellular hepatocyte organelles. Thus, in this model a component of cholestatic injury appears to have been caused by oxidant stress from a source outside of the hepatocyte.

Topics: Animals; Bile Ducts; Enzyme Inhibitors; Liver; Liver Diseases; Male; Oxidative Stress; Oxypurinol; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Little is known about the possible contribution of apoptosis to ischemia-reperfusion injury in human liver transplantation. Therefore, we studied postreperfusion surgical biopsy specimens of 16 human liver allografts using the TUNEL assay for in situ demonstration of apoptotic cells. In all patients, a variable proportion of hepatocytes and sinusoidal endothelial cells presented labeled nuclei. The mean +/- standard deviation percentages of positive hepatocytes were 18.7% +/- 12.2% in the whole section, 30.4% +/- 18.7% in the subcapsular region, 14.5% +/- 13.5% in the centrilobular zones, and 10.3% +/- 9.5% in the periportal zones. The percentage of positive hepatocytes were not correlated with the duration of cold ischemia but was higher in grafts harvested from donors with elevated preoperative aspartate aminotransferase (AST) levels. The percentage of positive hepatocytes was correlated with postoperative serum levels of AST (P = .015) and inversely correlated with postoperative serum levels of factor V (P = .019). Apoptotic biliary epithelial cells were detected in only 3 cases. In conclusion, apoptosis is a frequent event in postreperfusion biopsy specimens of liver allografts and probably contributes to preservation injury of hepatocytes.

Topics: Adenosine; Allopurinol; Apoptosis; Biopsy; Cryopreservation; Deoxyuracil Nucleotides; DNA Nucleotidyltransferases; Female; Glutathione; Humans; Immunoenzyme Techniques; Insulin; Liver; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Organ Preservation; Organ Preservation Solutions; Raffinose; Random Allocation; Reperfusion Injury; Transplantation, Homologous

The modulating effects of nitric oxide (NO) and reactive oxygen species on cocaine-induced hepatotoxicity were examined by measuring plasma alanine aminotransferase activity and by carrying out histological studies. Liver injury was induced by a single injection of cocaine in adult male ICR mice. Pretreatment with aminoguanidine (an inhibitor of NO synthase), N-methyl-D-glucamine dithiocarbamate complex with iron ion (II) (Fe2+(MGD)2, a trapping reagent of NO) or deferoxamine complex with iron ion (III) (Fe3+-deferoxamine, a scavenger of NO) produced a marked inhibition of the hepatotoxicity induced by cocaine. In addition, pretreatment with allopurinol (an inhibitor of xanthine oxidase) and 1,3-dimethylthiourea (a scavenger of hydroxyl radical) also produced a potent inhibition. These findings suggest that a hydroxyl radical produced by the reaction of NO and superoxide anion (O2-) via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity.

Topics: Allopurinol; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Cocaine; Enzyme Inhibitors; Guanidines; Liver; Liver Diseases; Male; Mice; Mice, Inbred ICR; Nitric Oxide; Nitric Oxide Synthase; Reactive Oxygen Species

Because reactive oxygen intermediates derived from xanthine oxidase may have an important role in the pathophysiology of lipopolysaccharide-mediated tissue injury, we studied hydrogen peroxide generation using 3-amino-1,2,4-triazole inactivation of hepatic catalase and the ratio of xanthine oxidase to xanthine dehydrogenase activity in rat livers after in vivo lipopolysaccharide administration. We also studied the effect of tungsten, a potent inhibitor of xanthine oxidase, on the toxicity of lipopolysaccharide. There was increased hydrogen peroxide production and enhanced proteolytic conversion from xanthine dehydrogenase to xanthine oxidase in rat livers after lipopolysaccharide administration. Feeding rats a tungsten-rich diet for 4 weeks greatly diminished hepatic xanthine oxidase activity and lessened the rise in intracellular hydrogen peroxide production after lipopolysaccharide treatment. Liver damage, as assessed by the serum transaminase levels and mortality, was also ameliorated by the tungsten-rich diet. These findings suggest that hydrogen peroxide derived from xanthine oxidase contributes to the development of systemic toxicity and liver damage after lipopolysaccharide administration.

Topics: Adenosine; Animals; Chemical and Drug Induced Liver Injury; Diet; Enzymes; Hydrogen Peroxide; Lipopolysaccharides; Liver Diseases; Male; Rats; Rats, Wistar; Reactive Oxygen Species; Tungsten; Xanthine Dehydrogenase; Xanthine Oxidase

Hepatic vascular exclusion allows the performance of major hepatic resections with minimal intraoperative blood loss. We have previously shown that normothermic ischemia can be tolerated by a healthy liver for up to 90 minutes, and this period is increased to 4 hours if the liver is cooled to 4 degrees C using University of Wisconsin solution.. This study assessed whether these techniques could be successfully applied for patients requiring resection of a diseased liver, which is more sensitive to ischemic damage. Between July 1990 and May 1994, 12 patients (6 men, 6 women; mean age, 57.8 years) in whom the planned hepatic resection was believed to require hepatic vascular exclusion for more than 1 hour were treated with perfusion with the University of Wisconsin solution. The surgical procedures were right hepatectomy (one patient), extended right hepatectomy (seven patients), and extended left hepatectomy (four patients). The underlying hepatic disease was cirrhosis or severe fibrosis with hepatocellular carcinoma (four patients), cholestasis (due to cholangiocarcinoma and biliary stricture, one patient each), and more than 30 percent steatosis after treatment of hepatic metastases with chemotherapy (six patients). The University of Wisconsin solution that had been cooled to 4 degrees C was perfused through a cannula placed in the portal vein or the hepatic arterial branch of the segment to be resected, but with flow directed toward the liver that should be retained and effluent fluid drained through a cavotomy. Before reperfusion, the liver was rinsed with Ringer's lactate solution, which was also 4 degrees C.. The mean duration of hepatic ischemia was 121 minutes (range, 65 to 250 minutes), and venovenous bypass was used in three cases. The mean amount of blood transfused intraoperatively was 4.3 +/- 4 U; four cases required no transfusion. One patient died on postoperative day seven of portal vein thrombosis. The median hospital stay was 21 days (range, 12 to 56 days). Postoperative complications consisted of pneumonia (one patient), liver insufficiency (one patient, who recovered spontaneously), and subphrenic abscess (one patient). The postoperative tests of hepatic function were altered to the same degree as that seen after hepatic vascular exclusion of less than 1-hour duration in healthy livers. All patients who left the hospital were alive at 1 year.. Cooling of the hepatic parenchyma allowed us to perform major hepatic resection in patients with diseased livers using hepatic vascular exclusion for longer than 1 hour without increased morbidity or mortality. However, because of particular difficulties due to the size or location of the lesions, the application of these new techniques should only be considered for the largest and most complex hepatic resections for which hepatic vascular exclusions longer than 1 hour are foreseen.

Topics: Adenosine; Adult; Aged; Allopurinol; Blood Loss, Surgical; Cryopreservation; Female; Follow-Up Studies; Glutathione; Hepatectomy; Hepatic Artery; Humans; Hypothermia, Induced; Insulin; Liver; Liver Circulation; Liver Diseases; Male; Middle Aged; Organ Preservation Solutions; Portal Vein; Raffinose; Reperfusion Injury; Tissue Preservation

Gender is currently not a criterion in the allocation of scarce donor organs. The purpose of this study was to determine the effects of gender on patient and graft survival, incidence of rejection, and postoperative complications after orthotopic liver transplantation.. During a 10-year period, 1138 liver transplants were performed on 1010 adult patients at Baylor University Medical Center. In this study, 994 patients with at least 6 months of posttransplant follow-up were reviewed. The four combinations of gender match and mismatch included: group 1, donor female to recipient female (n=229); group 2, donor female to recipient male (n= 126); group 3, donor male to recipient female (n=247); and group 4, donor male to recipient male (n=392). These groups were evaluated for patient survival, graft survival, episodes of rejection, incidence of chronic rejection, and postoperative complications.. All groups were similar with respect to recipient age, underlying medical condition, incidence of bacterial and viral infections, postoperative biliary complications, and the incidence of chronic rejection. Female recipients had the highest incidence of early rejection (0-6 months, 70%) compared with male recipients (60%, P<0.039). Postoperative vascular complication (10%) was highest in group 3 (P<0.01). The two-year graft survival rate for groups 1, 3, and 4 was 76.2%, 75.6%, and 73.5%, respectively. Group 2, donor female to recipient male, had a 2-year graft survival rate of 55.9% (P<0.0001). This finding is not explained by the incidence of early rejection. Chronic rejection does not appear to be contributory. The mean donor age for groups 1, 3, and 4 was 35.7, 25.8, and 30.4 years, respectively. The mean donor age for group 2 was slightly older, at 41.6 years (P<0.0001). This difference, while statistically significant, is of unknown clinical relevance. A multivariate analysis controlling for donor age confirmed the decreased graft and patient survival rates in the donor female to recipient male group.. The decreased graft survival rate in male recipients of female livers warrants further study and may argue for modifying the current management of adult male liver transplant recipients.

Topics: Adenosine; Adult; Allopurinol; Bacterial Infections; Biliary Tract Diseases; Female; Gender Identity; Glutathione; Graft Rejection; Graft Survival; Health Status; Humans; Hypertonic Solutions; Incidence; Insulin; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Organ Preservation; Organ Preservation Solutions; Racial Groups; Raffinose; Sex Characteristics; Survival Rate; Tissue Donors; Treatment Outcome; Virus Diseases

Topics: Adenosine; Allopurinol; Blood Loss, Surgical; Constriction; Embolism, Air; Follow-Up Studies; Glutathione; Hepatectomy; Hepatic Veins; Humans; Hypothermia, Induced; Insulin; Ischemia; Ligation; Liver Circulation; Liver Diseases; Liver Failure; Liver Neoplasms; Organ Preservation Solutions; Perfusion; Portal Vein; Raffinose; Survival Rate; Time Factors; Tissue Preservation; Vena Cava, Inferior

The relationship between lipid peroxidation and alterations in hepatic secretory function and microsomal function during hepatic ischemia/reperfusion was studied. Rats pretreated with free radical scavengers were subjected to 60 min of hepatic ischemia and to 1 and 5 h of reperfusion thereafter. Serum aminotransferase level and microsomal lipid peroxidation were markedly increased by ischemia/reperfusion. These increases were significantly attenuated by rebamipide, alpha-tocopherol or allopurinol. Bile flow and cholate output were markedly decreased by ischemia/reperfusion and free radical scavengers, especially rebamipide, restored their secretion. NADPH-cytochrome P450 reductase activity and cytochrome P450 content were decreased by ischemia/reperfusion. Rebamipide prevented the decrease of the NADPH-cytochrome P450 reductase activity but had little effect on the cytochrome P450 content. Aminopyrine N-demethylase activity was decreased and aniline p-hydroxylase was increased by ischemia/reperfusion, which were prevented by alpha-tocopherol and allopurinol, but not by rebamipide. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory function and microsomal function by increasing lipid peroxidation, and rebamipide significantly ameliorates these changes through its free radical scavenging activity.

Topics: Alanine; Alanine Transaminase; Allopurinol; Animals; Bile; Enzyme Inhibitors; Free Radical Scavengers; Lipid Peroxidation; Liver Diseases; Male; Microsomes, Liver; Mixed Function Oxygenases; NADPH-Ferrihemoprotein Reductase; Organ Size; Quinolones; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Vitamin E; Xanthine Oxidase

Topics: Animals; Free Radicals; Glutathione; Ischemia; Liver; Liver Diseases; Mitochondria, Liver; Rats; Reperfusion Injury; Ubiquinone; Vitamin E; Xanthine Dehydrogenase; Xanthine Oxidase

Xanthine oxidase catalyzes the biotransformation of many drugs, including the thiopurines and methyl-xanthines. We used a sensitive radiochemical assay to determine optimal conditions for the assay of human liver xanthine oxidase activity. We then used those assay conditions to study the nature and extent of individual variation of xanthine oxidase activity in 189 samples of hepatic tissue from patients undergoing clinically indicated partial hepatectomy or open liver biopsy. The average hepatic xanthine oxidase activity was 21% higher in samples from male patients than in those from female patients (1.27 +/- 0.43 [mean +/- SD, n = 92] versus 1.05 +/- 0.38 U/gm tissue [n = 97, p less than 0.0001], respectively). Seventy-nine of these tissue samples had been obtained from patients with normal liver function studies and normal serum creatinine values. Average xanthine oxidase activity in these 79 samples remained approximately 20% higher for men than for women (1.35 +/- 0.38 versus 1.12 +/- 0.33 U/gm tissue, respectively). Probit analysis of the data for samples from patients with normal liver function studies and normal creatinine values suggested the presence of a subgroup of samples with relatively low xanthine oxidase activity in 21% (9 of 42) of male patients and 27% (10 of 37) of female patients. These observations may have implications with regard to individual variation in the biotransformation of drugs metabolized by xanthine oxidase.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Biotransformation; Child; Female; Humans; Hydrogen-Ion Concentration; Kidney; Liver; Liver Diseases; Male; Middle Aged; Sex Factors; Specimen Handling; Uric Acid; Xanthine Oxidase

Serum uric acid was measured in 586 normal subjects and 1,220 hospitalized patients. Hypouricemia was noted in 0.34% of the normal subjects and 2.54% of the hospitalized patients. Among hospitalized patients with hypouricemia, 22 were on medication, including allopurinol, anticancer drugs, antibiotics and glucocorticoids. Twenty-one patients had liver disorders and 11 of them had received transfusions. Neoplastic diseases were noted in 14 patients. Thus, hypouricemia was found to be relatively common in hospitalized patients, and seems to be caused mainly by medication, neoplastic diseases, liver disorders and transfusions.

Topics: Adolescent; Adult; Aged; Allopurinol; Anti-Bacterial Agents; Antineoplastic Agents; Child; Female; Glucocorticoids; Hospitalization; Humans; Incidence; Japan; Liver Diseases; Male; Middle Aged; Neoplasms; Retrospective Studies; Transfusion Reaction; Uric Acid

Trolox, a hydrophilic analog of vitamin E, was reported to scavenge peroxyl radicals from artificial systems better than its parent compound. Here we examined the possible cytoprotective effect of Trolox in cultured hepatocytes and in the rat liver. In cultured rat hepatocytes, 0.5 to 16 mmol/L Trolox (with optimum between 1 to 2 mmol/L) was observed to prolong the survival of cells exposed to oxyradicals generated with xanthine oxidase-hypoxanthine. The protection by 1 mmol/L Trolox surpassed that provided by either ascorbate, mannitol, superoxide dismutase and/or catalase--each at a level giving its maximal protection in the same system. In both a global and partial model of hepatic ischemia-reperfusion in rats, infusion of Trolox (7.5 to 10 mumol/kg body weight) just before reflow reduced by greater than 80% the liver necrosis sustained in untreated (no Trolox) control rats. Such organ salvage was apparently accompanied by approximately 50% reduction in the amount of hepatic conjugated dienes, which were quantified by a highly specific radiochemical assay. Since conjugated dienes are presumed to be good "markers" of oxyradical damage, our data may have provided a semiquantitative link between free radical-induced necrosis and its chemical imprint in vivo. The data also indicated a relatively rapid and potent antioxidant-like action by Trolox on rat hepatocytes and on the postischemic reperfused rat liver.

Topics: Animals; Cells, Cultured; Chromans; Free Radicals; Hypoxanthine; Hypoxanthines; Ischemia; Liver; Liver Diseases; Male; Rats; Rats, Inbred Strains; Reperfusion Injury; Xanthine Oxidase

Acetaminophen (500 mg/kg i.p.) induced hepatotoxicity in fasted ICR mice in vivo. Acetaminophen also caused a long-lasting 50% reduction of the hepatic ATP content, an irreversible loss of hepatic xanthine dehydrogenase activity and a transient increase of the xanthine oxidase activity. All effects occurred before parenchymal cell damage, i.e., the release of cellular enzymes. The hepatic content of GSH and GSSG was initially depleted by acetaminophen without affecting the GSSG:GSH ratio (1:200), however, during the recovery phase of the hepatic GSH levels the GSSG content increased faster than GSH, resulting in a GSSG:GSH ratio of 1:18 24 h after acetaminophen administration. The mitochondrial GSSG content increased from 2% in controls to greater than 20% in acetaminophen-treated mice. The extremely elevated tissue GSSG levels were accompanied by a 4-fold increase of the plasma GSSG concentrations but not by an enhanced biliary efflux, although hepatic GSSG formation and biliary excretion were not affected by acetaminophen. Allopurinol protected dose-dependently against acetaminophen-induced cell injury, the loss of ATP and the increase of the GSSG content in the total liver and in the mitochondrial compartment without inhibiting reactive metabolite formation. High, protective as well as low, nonprotective doses of allopurinol almost completely inhibited hepatic xanthine oxidase and dehydrogenase activity, but only high doses prevented the increase of the mitochondrial GSSG content. The data indicate a long-lasting, primarily intracellular oxidant stress during the progression phase of acetaminophen-induced cell necrosis. The protective effect of allopurinol is unlikely to involve the inhibition of reactive oxygen formation by xanthine oxidase but could be the result of its antioxidant property.

Topics: Acetaminophen; Adenosine Triphosphate; Alanine Transaminase; Allopurinol; Animals; Chemical and Drug Induced Liver Injury; Liver; Liver Diseases; Male; Mice; Mice, Inbred Strains; Oxidation-Reduction; Oxygen; Xanthine Dehydrogenase; Xanthine Oxidase

Liver function can be assessed by administering an exogenous substance to quantify changes in hepatic blood flow, uptake, biotransformation, and excretion. Characterization of drug half-life, clearance, and product formation rates are possible methods for measuring hepatic efficiency. Allopurinol and caffeine have been used to measure metabolite formation followed by renal elimination of both parent substance and metabolite. Sorbitol, a substance with high intrinsic clearance, can reflect liver blood flow, while trimethadione, a low-extraction drug, has been used to measure liver enzyme capacity. Metabolites from lidocaine, methacetin, and aminopyrine have been measured in serum, urine, and breath tests. Salivary clearance measurements of caffeine and antipyrine are reported as suitable for routine use. Genetic diversity of isoenzymes and the many metabolic processes used by hepatocytes make it extremely difficult to quantify functional changes with one substance. Combinations of model substrates have been suggested to assess the many hepatic processes.

Topics: Acetamides; Adult; Allopurinol; Aminopyrine; Caffeine; Half-Life; Humans; Indocyanine Green; Lidocaine; Liver; Liver Circulation; Liver Diseases; Liver Function Tests; Metabolic Clearance Rate; Middle Aged; Oxypurinol; Pyrimidines; Sorbitol

Topics: Adenosine; Adolescent; Adult; Aged; Allopurinol; Child; Child, Preschool; Glutathione; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Insulin; Liver Diseases; Liver Function Tests; Liver Transplantation; Middle Aged; Organ Preservation Solutions; Raffinose; Solutions; Tissue Preservation; Transplantation, Homologous

Topics: Adenosine; Adult; Allopurinol; Child; Glutathione; Graft Survival; Humans; Insulin; Liver; Liver Diseases; Liver Transplantation; Organ Preservation; Organ Preservation Solutions; Raffinose; Solutions; Tissue Preservation

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Gout; Humans; Liver Diseases; Male; Necrosis

A newly developed liver function test was performed on 18 apparently healthy individuals and 29 patients with liver disease. After intravenous injection of a low dose allopurinol (17.1 mumol/kg body mass), blood specimens were collected during 1 h. Plasma analyses of allopurinol and its metabolite oxipurinol were performed and the data were processed by means of a computer-based biodynamic model. This modelling approach makes it possible to estimate parameters, containing information about liver perfusion, hepatocyte membrane transport and hepatocyte cell mass. One parameter (kA31) showed complete discrimination between the reference sample group of healthy individuals and patients with severe liver dysfunction. In a reference sample group of patients with slightly to moderately reduced liver function, only a few patients (5/20) had a kA31 value over the decision limit. In this respect, the allopurinol loading test is superior to the conventional intravenous galactose tolerance test.

Topics: Adolescent; Adult; Aged; Allopurinol; Evaluation Studies as Topic; Female; Galactosemias; Humans; Injections, Intravenous; Liver Diseases; Liver Function Tests; Male; Middle Aged; Oxypurinol; Time Factors

Using isolated hemoglobin-free perfused rat livers we investigated the hepatotoxic effects of hypoxia, ethanol or the combination of both. Hypoxia only (90 min) led to a weak toxicity as evidenced by the efflux of the enzymes glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH). This toxic effect was slightly higher in livers treated with ethanol (3 g/l) under normoxic conditions. Ethanol added under hypoxic conditions, however, showed a strong hepatotoxic effect. Under hypoxic conditions, lactate + pyruvate production was increased fivefold over control, indicating that glycolysis was more effectively undergone as main source of energy. Addition of ethanol suppressed this effect, indicating that ethanol inhibited glycolysis. These results indicate that ethanol potentiates hypoxic liver damage by inhibiting the main metabolic pathway yielding ATP under low oxygen tension resulting in a severe energy deficit. Allopurinol (100 mg/l) inhibited the toxic effects seen with ethanol + hypoxia. Also, the inhibitory action of ethanol on glycolysis was antagonized. Our results are consistent with the following model: hypoxia converts NAD-dependent xanthine dehydrogenase (XD) into the oxygen-dependent xanthine oxidase (XO). Due to hypoxia and ethanol, purine metabolites and acetaldehyde accumulate and are metabolized via XO. This process leads to the production of oxygen radicals which most probably mediate both the inhibition of glycolysis and the direct toxic effects towards liver cells.

Topics: Acetaldehyde; Adenosine Triphosphate; Alanine Transaminase; Allopurinol; Animals; Ethanol; Glycolysis; Hypoxia; L-Iditol 2-Dehydrogenase; Liver; Liver Diseases; Male; Purines; Rats; Rats, Inbred Strains; Xanthine Oxidase

A new method for the determination of xanthine oxidase activity, based on the oxidation of 2,2'-azino-di(3-ethylbenzthiazoline-6-sulphonate) (ABTS) by use of uricase and peroxidase, is described. The absorbance increase of the oxidized form of ABTS, measured after 10 min at 410 nm is proportional to xanthine oxidase activity. The method is sensitive, precise (CV below 8.3%), and linear up to 20 U/l. The analytical recovery of the ABTS-method was quantitative. Comparison with the UV and colorimetric NBT-method gave good correlation (r greater than or equal to 0.984). Reference values for serum xanthine oxidase activities determined with the new ABTS-method on 83 healthy persons are 0 to 1.20 U/l.

Topics: Adolescent; Adult; Benzothiazoles; Chromogenic Compounds; Female; Humans; Liver; Liver Diseases; Male; Middle Aged; Reference Values; Spectrophotometry; Sulfonic Acids; Xanthine Oxidase

Topics: Allopurinol; Humans; Injections, Intravenous; Kinetics; Liver Diseases; Liver Function Tests; Models, Biological; Oxypurinol

Hepatic fibrin-ring granulomas were found in a 35-yr-old man who developed fever, myalgias, rash, eosinophilia, and abnormal liver function tests 4 wk after the beginning of allopurinol treatment. All clinical and biochemical abnormalities spontaneously resolved within 6 wk after cessation of therapy. There was no evidence for Q fever or Hodgkin's disease, which are the recognized causes of hepatic fibrin-ring granulomas. It is suggested that allopurinol hypersensitivity might be an additional cause of these peculiar granulomas.

Topics: Adult; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Fibrin; Granuloma; Humans; Liver; Liver Diseases; Male

In this new method for determining serum guanase activity by use of the Hitachi 736-40 automated analyzer, serum is incubated with a mixture of xanthine oxidase, superoxide dismutase, and catalase; a reagent containing KCN, guanine, nitrotetrazolium blue, and Triton X-100 is added; and the increase in absorbance at 570 and 660 nm is measured for 2.4 min. Only 20 microL of sample is required, and results are linearly related to the activity concentration of guanase up to 30 U/L. Within-run and day-to-day precision (CV) was respectively 2.6 to 4.2% and 3.5 to 5.5% over 0-30 U of guanase activity per liter. The normal reference interval, as calculated from data on 40 healthy persons, is 0.1 to 2.2 U/L. Results correlate well (r = 0.997) with those by a kinetic method (Clin Chem 27: 560, 1981). The guanase activity of 150 samples can be measured within 1 h by this method.

Topics: Adult; Aminohydrolases; Autoanalysis; Catalase; Female; Guanine Deaminase; Humans; Hydrogen-Ion Concentration; Kinetics; Liver; Liver Diseases; Male; Middle Aged; Nitroblue Tetrazolium; Octoxynol; Polyethylene Glycols; Reference Values; Spectrophotometry; Superoxides; Time Factors; Xanthine; Xanthine Oxidase; Xanthines

We have investigated the possible protective effect of superoxide dismutase and allopurinol in a rat model of mild and severe hepatic necrosis produced by Corynebacterium parvum with or without endotoxin. Histology showed a sinusoidal mononuclear cell infiltrate with multiple granulomata but variable degrees of hepatic necrosis. In the severe hepatic injury model there was a reduction in mortality, associated with a decrease in histologic and biochemical evidence of hepatic necrosis, after treatment with superoxide dismutase. This protective effect was not demonstrated with partially heat-inactivated superoxide dismutase. In the mild hepatic injury model similar trends in reduction of serum levels of hepatic enzymes were observed after treatment with both superoxide dismutase and allopurinol. These results indicate that oxygen-derived free radicals may play an important role in the pathogenesis of hepatic injury in the rat.

Topics: Alanine Transaminase; Allopurinol; Animals; Disease Models, Animal; Endotoxins; Free Radicals; Hepatitis; Isocitrate Dehydrogenase; Liver; Liver Diseases; Necrosis; Propionibacterium acnes; Rats; Rats, Inbred Strains; Superoxide Dismutase; Superoxides; Xanthine Oxidase

The metabolic disappearance of caffeine from blood is subject to substantial inter- and intra-individual variation. Smoking of cigarettes and other inducers of aryl hydrocarbon hydroxylase tend to enhance the caffeine metabolism; pregnancy, the use of oral contraceptives, and various kinds of liver disease prolong the caffeine half-life. A genetic component affecting caffeine half-life has not yet been systematically searched for, but might be expected to affect the response to cigarette smoke and similar inducing agents, rather than to provide direct control of caffeine metabolism. The secondary metabolisms of the primary caffeine metabolites are strongly affected by the well-known genetic polymorphism of the N-acetyltransferase of human liver (a polymorphism originally discovered by studies of isoniazid metabolism). Since the proportion of slow acetylators differs in different ethnic populations, many ethnic differences in the ultimate fate of caffeine are to be expected. An observed difference of paraxanthine excretion between Caucasian and Oriental subjects might reflect a difference in the capacity for renal tubular reabsorption of that substance, but further metabolic differences cannot be excluded. The renal elimination of the dimethylxanthines is urinary flow dependent while that of the water soluble metabolites 1-methylxanthine and AFMU (5-acetylamino-6-formylamino-3-methyluracil) is not. Thus, the urinary metabolite pattern can be expected to vary from time to time. However, habitual coffee intake does not affect the metabolite pattern of caffeine.

Topics: Acetylation; Biotransformation; Caffeine; Dealkylation; Female; Half-Life; Humans; Kinetics; Liver Diseases; Male; Phenotype; Pregnancy; Racial Groups; Smoking; Time Factors; Xanthine Oxidase

Older patients with type I glycogen storage disease (GSD) develop hepatic adenomas that may undergo malignant transformation. Despite their similarity to oral contraceptive-related hepatic tumors, only one previous report has even mentioned hemorrhage in GSD-related hepatic tumors. We recently followed a 20-year-old patient with type Ia GSD and a 10 cm focal defect in the left lobe of the liver; angiography suggested that this was a benign adenoma. At 22 years of age, after an acute symptomatic episode, repeat studies (ultrasonography and angiography) revealed a 2 cm increase in diameter of the hepatic mass. Imminent tumor rupture was of grave concern; thus the patient was admitted to the hospital and given 2 weeks of constant glucose administration by central venous line in the hope of improving her metabolic abnormalities. After resolution of the coagulopathy and metabolic disorders, the patient safely underwent surgical enucleation of the tumor. Pathologic examination of the tumor revealed that the patient had indeed hemorrhaged into a typical hepatic adenoma that had focuses of hepatocellular dysplasia. She has done well without evidence of tumor recurrence for 3 years since the operation. We conclude that hemorrhage and malignant transformation are potential complications of GSD-related hepatic adenomas. This conclusion underscores the importance of following these patients closely as they age. Nocturnal nasogastric feeding should be considered in the hope of preventing a tumor or inducing regression. Acute symptomatic attacks should be evaluated promptly for possible tumor hemorrhage.

Topics: Adenoma; Adolescent; Adult; Allopurinol; Child; Follow-Up Studies; Glucose; Glycogen Storage Disease Type I; Hemorrhage; Humans; Infant; Infusions, Parenteral; Liver Diseases; Liver Neoplasms; Time Factors

Topics: Allopurinol; Biopsy, Needle; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Glycogen Storage Disease; Hemangiosarcoma; Hemochromatosis; Hepatitis, Alcoholic; Hepatitis, Chronic; Humans; Leprosy; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Neoplasms; Peliosis Hepatis

Allopurinol hepatotoxicity occurred in two patients. Data from the literature suggest that allopurinol can occasionally cause liver injury, particularly in persons receiving diuretic drugs or with compromised renal function. Clinical and laboratory findings are consistent with hepatocellular injury mediated by a hypersensitivity reaction. Most patients recover when the drug is withdrawn; the possible benefits of corticosteroid treatment remain to be established.

Topics: Adrenal Cortex Hormones; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Humans; Liver Diseases; Male; Necrosis

A spectrophotometric method is described for the determination of 5'-nucleotidase. In combination with the enzymes nucleoside phosphorylase and xanthine oxidase, inosine, formed by hydrolysis of 5'-IMP by 5'-nucleotidase, is cleaved phosphorolytically to hypoxanthine, which is oxidized to uric acid. In the presence of ethanol, the hydrogen peroxide formed is reduced by catalase and equivalent amounts of acetaldehyde are produced. The aldehyde is dehydrogenated (NADP-dependent) by aldehyde dehydrogenase and the production rate of NADPH is recorded at 334 nm. The inhibition of the unspecific cleavage of 5'-IMP by phosphatases is examined critically.

Topics: 5'-Nucleotidase; Aldehyde Oxidoreductases; Alkaline Phosphatase; Bone Diseases; Inosine Monophosphate; Liver Diseases; Nucleotidases; Phosphates; Purine-Nucleoside Phosphorylase; Spectrophotometry, Ultraviolet; Xanthine Oxidase

Topics: Acute Disease; Clinical Enzyme Tests; Diagnosis, Differential; Humans; Liver Diseases; Spectrometry, Fluorescence; Xanthine Oxidase

Hypouricaemia (blood level blow 2 mg/100 ml or 12 mumol/100 ml) is rarely observed, i.e., in less than 1% of hospitalized patients. Hypouricaemia can be induced by any of three mechanisms: a decrease in uric acid synthesis due to deficient xanthine oxydase (e.g., hereditary xanthinuria, severe liver disease, treatment with allopurinol); increased uricolysis due to drug therapy; increased urinary excretion of uric acid. This increased urinary excretion is due to abnormal uric acid transport in the proximal tubule. It is sometimes observed alone (primary hereditary anomaly of tubular uric acid transport, severe liver disease or neoplasia, drugs, or contrast media). It can also be observed in association with other proximal tubular anomalies, constituting a Fanconi syndrom. Among observations of hypouricaemia, 50% result from drug therapy and approximately 30% are secondary to liver diseases or neoplasia. It has no special clinical consequence. Nevertheless, the observation of hypouricaemia in a patient should indicate the possibility of drug intoxication or an underlying disease, in particular neoplasia. Measurement of uric acid clearance is a simple method of determining the mechanism responsible and of guiding diagnosis.

Topics: Allopurinol; Fanconi Syndrome; Humans; Liver Diseases; Neoplasms; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid; Xanthines

A 36-year-old man had pain in both knees and an elevated uric acid concentration; his liver function was normal. Allopurinol therapy was started, 100 mg twice daily. After one month fever, lethargy, and severe polyarthralgia developed. On admission to our hospital liver function was abnormal, and a liver biopsy specimen showed granulomas with cholangitis and pericholangitis. He also had lymphopenia with a reduced number of T cells and granulomas in the bone marrow. One month after discontinuation of allopurinol therapy the patient was clinically well with normal liver function and a normal lymphocyte count. A repeated liver biopsy specimen showed normal liver tissue with no granulomas. The onset of the symptoms and findings shortly after the initiation of allopurinol therapy, and their disappearance after the discontinuation of therapy suggest a drug-induced hypersensitivity.

Topics: Allopurinol; Chemical and Drug Induced Liver Injury; Cholangitis; Granuloma; Humans; Liver Diseases; Male; Middle Aged; Sarcoidosis

Topics: Clinical Enzyme Tests; Humans; Liver Diseases; Xanthine Oxidase

Halothan anesthesia was found to be hapatotoxic in the rat, as demonstrated by a significant elevation of serum xanthine oxidase (SXO) level. SXO appeared to be more sensitive marker of liver damage than serum glutamic oxalacetic transaminase. SXO was found to be elevated also following exposure to relative hypoxia.

Topics: Anesthesia, General; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Female; Halothane; Hypoxia; Liver Diseases; Male; Rats; Xanthine Oxidase

Topics: Humans; Liver Diseases; Male; Purines; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Humans; Jaundice; Liver Diseases; Xanthine Oxidase

Topics: Arginase; Biopsy; Child; Child, Preschool; Chronic Disease; Female; Hepatitis; Humans; Infant; Infant, Newborn; Infections; Liver; Liver Cirrhosis; Liver Diseases; Male; Nephrotic Syndrome; Nutrition Disorders; Xanthine Oxidase

Topics: Bile Ducts; Biliary Tract Diseases; Clinical Enzyme Tests; Humans; Liver Diseases; Lung Abscess; Spectrophotometry; Stomach Diseases; Thrombosis; Xanthine Oxidase

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Humans; Hydroxyurea; Iatrogenic Disease; Leukemia, Myeloid; Liver; Liver Diseases; Male; Prednisone; Splenomegaly; Vincristine

Topics: Alanine Transaminase; Alkaline Phosphatase; Anemia, Hemolytic; Aspartate Aminotransferases; Carbon Isotopes; Cholestasis; Female; Hepatitis; Humans; Infectious Mononucleosis; Liver Cirrhosis; Liver Diseases; Male; Myocardial Infarction; Neoplasms; Typhoid Fever; Xanthine Oxidase

Topics: Allopurinol; Aspirin; Contrast Media; Depression, Chemical; Diet; Female; Guaifenesin; Humans; Liver Diseases; Male; Neoplasms; Osmolar Concentration; Uric Acid

Topics: Aminohydrolases; Glutamate Dehydrogenase; Guanine; Humans; Kinetics; Liver Diseases; Mathematics; Methods; NAD; Spectrophotometry, Ultraviolet; Xanthine Oxidase

Topics: Aged; Alcoholism; Allopurinol; Arrhythmias, Cardiac; Chloral Hydrate; Colchicine; Digoxin; Drug Synergism; Gastrointestinal Hemorrhage; Gout; Hospitals, Teaching; Humans; Liver Diseases; Male; Middle Aged; Nitroglycerin; Patient Care Team; Pharmacists; Pharmacy Service, Hospital; Quinidine; Warfarin; Washington

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cholestasis; Chromatography, Gel; Female; Hemochromatosis; Hepatic Encephalopathy; Hepatitis; Hepatitis A; Humans; Intestinal Diseases; Liver Cirrhosis; Liver Diseases; Male; Myocardial Infarction; Rats; Spectrophotometry; Xanthine Oxidase

Topics: Adolescent; Adrenocortical Hyperfunction; Adult; Aged; Allopurinol; Child; Diet Therapy; Female; Femur Head; Femur Head Necrosis; Hematologic Diseases; Humans; Hyperlipidemias; Lipids; Liver Diseases; Male; Metabolic Diseases; Middle Aged; Phospholipids; Uric Acid

Topics: Adolescent; Adult; Aged; Autoradiography; Binding Sites; Deferoxamine; Humans; Iron; Iron Chelating Agents; Liver; Liver Diseases; Middle Aged; Pentetic Acid; Transferrin; Xanthine Oxidase

Topics: Aged; Alcoholism; Allopurinol; Ammonia; Humans; Liver Diseases; Male; Middle Aged

Topics: Animals; Carbon Tetrachloride Poisoning; Chromatography; Cytochromes; Female; Liver Diseases; Male; Microsomes; NAD; Oxidoreductases; Rats; Starvation; Transaminases; Xanthine Oxidase

Topics: Alanine Transaminase; Aspartate Aminotransferases; Clinical Enzyme Tests; Diagnosis; Hepatitis; Hepatitis A; Humans; Jaundice; Jaundice, Obstructive; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Myocardial Infarction; Statistics as Topic; Xanthine Oxidase

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cholestasis; Hepatitis A; Hepatitis, Animal; Humans; Liver Cirrhosis; Liver Diseases; Mice; Rats; Urate Oxidase; Xanthine Oxidase