nitrophenols and Body-Weight

4-Nitrophenol (PNP) is well known as an environmental endocrine disruptor. The aim of this study was to clarify the mechanism of PNP-induced liver damage and determine the regulatory involvement of the aryl hydrocarbon receptor (AhR) signaling pathway and associated gene expression. Immature male Wistar-Imamichi rats (28 days old) were randomly divided into control and PNP groups, which consisted of 1- and 3-day exposure (1 DE and 3 DE, respectively) and 3-day exposure followed by 3-day recovery (3 DE + 3 DR), groups. Each group was administered the vehicle or PNP (200 mg kg

Topics: Animals; Body Weight; Cytochrome P-450 CYP1A1; Endocrine Disruptors; Gene Expression Regulation; Glutathione Transferase; Liver; Male; Nitrophenols; Organ Size; Rats, Wistar; Receptors, Aryl Hydrocarbon; Signal Transduction

In the present study, to evaluate embryonic toxicity and the thyroid-disrupting effects of 2,4-dichloro-6-nitrophenol (DCNP), embryos and adults of Chinese rare minnow (Gobiocypris rarus) were exposed to 2, 20, and 200μg/L DCNP. In the embryo-larval assay, increased percentages of mortality and occurrence of malformations, decreased percentage of hatching, and decreased body length and body weight were observed after DCNP treatment. Moreover, the whole-body T3 levels were significantly increased at 20 and 200μg/L treatments, whereas the T4 levels were markedly decreased significantly (p<0.05) for all DCNP concentrations. In the adult fish assay, plasma T3 levels were significantly increased whereas plasma T4 levels were significantly reduced in the fish treated with 20 and 200μg/L (p<0.05). In addition, DCNP exposure significantly changed the transcription levels of thyroid system related genes, including dio1, dio2, me, nis, tr, and ttr. The increased responsiveness of thyroid hormone and mRNA expression levels of thyroid system related genes suggested that DCNP could disrupt the thyroid hormone synthesis and transport pathways. Therefore, our findings provide new insights of DCNP as a thyroid hormone-disrupting chemical.

Topics: Animals; Body Weight; Cyprinidae; Embryo, Nonmammalian; Gene Expression Regulation; Larva; Nitrophenols; RNA, Messenger; Thyroid Hormones; Transcription, Genetic

The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.

Topics: Animals; Animals, Suckling; Body Weight; Carcinogenesis; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme Inducers; Diethylnitrosamine; Inactivation, Metabolic; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Microsomes, Liver; Nitrophenols; Pyridines; Tumor Burden

Nitrobenzene is a synthetic compound, more than 95% of which is used in the production of aniline. Nitrobenzene has been demonstrated to be substantially metabolized to p-Nitrophenol, p-Aminophenol and p-Nitroaniline in food animals (e.g., bovines, fowls). There have been no studies on the acute toxicity and the mutagenesis of the mixture of the three metabolites mentioned above. The aim of the present study is to testify the acute toxicity and the mutagenesis of the three metabolites mixture. Seventy Kunming mice (half male, half female) received an intragastric administration exposure to metabolites-containing suspension of 750, 638, 542, 461, 392, 333 mg kg(-1) body weight and 0.5% sodium carboxymethyl cellulose (control), followed by a 14-day observation. The medial lethal dose (LD(50)) concentration for nitrobenzene metabolites mixture in this study was 499.92 mg/kg. Their mutagenic toxicology was studied through micronucleus and sperm abnormality test. Kunming mice were twice intragastrically exposed to 1/5 LD(50), 1/10 LD(50), 1/20 LD(50) mg kg(-1) nitrobenzene metabolites-containing suspension spaced 24-h apart. Cyclophosphamide, pure water and sodium carboxymethyl cellulose served as doses of the positive group, the negative group and the solvent control group, respectively. The incidence of micronucleus and sperm abnormality increased significantly in the 1/5 LD(50) and 1/10 LD(50) group compared with the negative and solvent control group. A dose-related increase in the incidence of micronucleus and sperm abnormality was noted. In conclusion, the three metabolites mixture of nitrobenzene was secondary toxicity and mutagenic substances in mice.

Topics: Aminophenols; Aniline Compounds; Animals; Body Weight; Bone Marrow Cells; Female; Lethal Dose 50; Male; Mice; Micronucleus Tests; Mutagenesis; Mutagens; Nitrobenzenes; Nitrophenols; Spermatozoa; Toxicity Tests, Acute

Our previous studies have shown that major metabolites of nitrobenzene in bovine and fowl were p-nitrophenol, p-aminophenol, and p-nitroaniline. There are few reports about the subacute toxicity of the three metabolites. The aim of this study was to investigate the subacute toxicity of these compounds. A suspension containing three metabolites at 50, 25, and 5 mg kg(-1) body weight was administrated introgastrically to Sprague-Dawley rats of both sexes for 4 weeks. All four groups survived to the end of the 4-week treatment period. Compared to the control group, there was a significant difference in body-weight increases in rats administered nitrobenzene metabolites at 50 and 25 mg kg(-1) (P < 0.01). ALT, AST, ALP, T-CHO, TP, albumin, and creatinine were significantly increased in the 50-mg kg(-1) group and tended to increase in the 25-mg kg(-1) group, compared with controls. There was no significant difference in glucose between treatment groups and controls. RBC counts and concentration of Hb decreased significantly in the 50- and 25-mg kg(-1) groups, compared with controls, whereas WBC and Ret counts increased in the 50- and 25-mg kg(-1) groups and LYM only in the 50-mg kg(-1) group. There were no significant differences in MONO and neutrophil counts, compared with controls. Methemoglobin concentrations were significantly increased on day 21 of treatment in the 50-mg kg(-1) group and on day 28 in the 25- and 50-mg kg(-1) groups. The subacute toxicity was characterized by lesions affecting the liver, kidneys, spleen, cerebellum, and hematopoietic system.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Aminophenols; Aniline Compounds; Animals; Aspartate Aminotransferases; Blood Cell Count; Body Weight; Cholesterol; Creatinine; Female; Male; Methemoglobin; Nitrobenzenes; Nitrophenols; Organ Size; Random Allocation; Rats; Rats, Sprague-Dawley; Serum Albumin

Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.. We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.. T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Topics: Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Female; Mibefradil; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocytes, Cardiac; Nitrendipine; Nitrophenols; Organophosphorus Compounds; Patch-Clamp Techniques

We previously reported an ontogeny model of hepatic cytochrome P450 (P450) activity that predicts in vivo P450 elimination from in vitro intrinsic clearance. The purpose of this study was to conduct investigations into key assumptions of the P450 ontogeny model using the developing rat model system. We used two developmentally dissimilar enzymes, CYP2E1 and CYP1A2, and male rats (n = 4) at age groups representing critical developmental stages. Total body and liver weights and hepatic microsomal protein contents were measured. Following high-performance liquid chromatography analysis, apparent K(M) and V(max) estimates were calculated using nonlinear regression analysis for CYP2E1- and CYP1A2-mediated chlorzoxazone 6-hydroxylation and methoxyresorufin O-dealkylation, and V(max) estimates for p-nitrophenol and phenacetin hydroxylations, respectively. Hepatic scaling factors and V(max) values provided estimates for infant scaling factors (ISF). The data show microsomal protein contents increased with postnatal age and reached adult values after postnatal day (PD) 7. Apparent K(M) values were similar at all developmental stages except at < or =PD7. Developmental increases in probe substrate V(max) values did not correlate with the biphasic increase in immunoquantifiable P450. The activity of two different probe substrates for each P450 covaried as a function of age. A plot of observed ISF values as a function of age reflected the developmental pattern of rat hepatic P450. In summation, these observations diverge from several of the model's assumptions. Further investigations are required to explain these inconsistencies and to investigate whether the developing rat may provide a predictive paradigm for pediatric risk assessment for P450-mediated elimination processes.

Topics: Age Factors; Aging; Animals; Body Weight; Chlorzoxazone; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2E1; Cytochromes; Dealkylation; Hydroxylation; Isoenzymes; Kinetics; Liver; Male; Microsomes, Liver; Models, Biological; Nitrophenols; Organ Size; Oxazines; Phenacetin; Proteins; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Risk Assessment; Substrate Specificity

The aim of this study was to evaluate diazepam and oxazepam as cytochrome P450 inducers at doses previously shown to cause liver tumors in mice but not rats. In rats, diazepam and oxazepam induced CYP2B, and were as effective as phenobarbital despite lacking phenobarbital's tumor-promoting effect in rats. In mice, diazepam and oxazepam induced both CYP2B and CYP4A at dietary doses associated with liver tumor formation. It remains to be determined why diazepam and oxazepam induce CYP4A in mice but not rats and whether this difference accounts for the apparent species difference in the tumor-promoting activity of diazepam and oxazepam.

Topics: Animals; Benzodiazepines; Blotting, Western; Body Weight; Carcinogens; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2B1; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Diazepam; Hypnotics and Sedatives; Immunohistochemistry; Isoenzymes; Lauric Acids; Liver Neoplasms; Male; Mice; Microsomes, Liver; Nitrophenols; Organ Size; Oxazepam; Phenobarbital; Rats; Rats, Sprague-Dawley

To elucidate the comparative susceptibility of newborn rats to chemicals, newborn and young animals were administered six industrial chemicals by gavage from postnatal days (PND) 4 to 21, and for 28 days starting at 5-6 weeks of age respectively, under the same experimental conditions as far as possible. As two new toxicity endpoints specific to this comparative analysis, presumed no-observed-adverse-effect-levels (pNOAELs) were estimated based on results of both main and dose-finding studies, and presumed unequivocally toxic levels (pUETLs) were also decided. pNOAELs for newborn and young rats were 40 and 200 for 2-chlorophenol, 100 and 100 for 4-chlorophenol, 30 and 100 for p-(alpha,alpha-dimethylbenzyl) phenol, 100 and 40 for (hydroxyphenyl)methyl phenol, 60 and 12 for trityl chloride, and 100 and 300 mg/kg/day for 1,3,5-trihydroxybenezene, respectively. To determine pUETLs, dose ranges were adopted in several cases because of the limited results of experimental doses. Values for newborn and young rats were thus estimated as 200-250 and 1000 for 2-chlorophenol, 300 and 500 for 4-chlorophenol, 300 and 700-800 for p-(alpha,alpha-dimethylbenzyl) phenol, 140-160 and 1000 for (hydroxyphenyl)methyl phenol, 400-500 and 300 for trityl chloride, and 500 and 1000 mg/kg/day for 1,3,5-trihydroxybenzene, respectively. In most cases, newborn rats were 2-5 times more susceptible than young rats in terms of both the pNOAEL and the pUETL. An exception was that young rats were clearly more susceptible than their newborn counterparts for trityl chloride.

Topics: Animals; Animals, Newborn; Benzene Derivatives; Body Weight; Chlorophenols; Dose-Response Relationship, Drug; Female; Kidney; Liver; Male; Nitrophenols; No-Observed-Adverse-Effect Level; Organ Size; Phenols; Rats; Rats, Sprague-Dawley; Stomach; Trityl Compounds

Efonidipine, a calcium antagonist, has been reported to dilate not only afferent but also efferent arterioles, thereby reducing glomerular hydrostatic pressure. We investigated the effect of chronic treatment with efonidipine or lisinopril on the afferent and efferent arteriolar diameters by the vascular cast technique. Four-week-old spontaneously hypertensive rats (SHR) were divided into three groups: untreated, efonidipine (25 mg/kg/day)-treated, and lisinopril (3 mg/kg/day)-treated. At 22 weeks of age, the renal vasculatures were fixed at the maximally dilated condition. The morphometrical measurements showed that the treatments with efonidipine and lisinopril caused structural alteration of the vasculature, resulting in significantly greater efferent arteriolar diameters than in untreated SHR. In addition, lisinopril-treated rats had wider afferent lumina. The renoprotective effect of efonidipine and lisinopril might be partly due to the structurally larger efferent arteriolar lumen.

Topics: Animals; Arterioles; Blood Pressure; Body Weight; Calcium Channel Blockers; Corrosion Casting; Dihydropyridines; Hypertension, Renal; Kidney Glomerulus; Male; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Renal Circulation

The toxicities of 4-nitrophenol and 2,4-dinitrophenol in newborn and young rats was examined and the susceptibility of newborn rats was analyzed in terms of presumed unequivocally toxic and no observed adverse effect levels (NOAELs). In the 18-day repeated dose newborn rat study, 4-nitrophenol was orally given from Day 4 to Day 21 after birth but did not induce any toxicity up to 160 mg/kg in the main study, although it induced death in one of six males at 160 mg/kg, and three of six males and one of six females at 230 mg/kg in a prior dose-finding study. In the 28-day repeated dose oral toxicity study starting at 6 weeks of age, 4-nitrophenol caused the death of most males and females at 1,000 mg/kg but was not toxic at 400 mg/kg except for male rat-specific renal toxicity. As unequivocally toxic levels were considered to be 230 mg/kg/day in newborn rats and 600 to 800 mg/kg/day in young rats, and NOAELs were 110 mg/kg/day in newborn rats and 400 mg/kg/day in young rats, the susceptibility of the newborn to 4-nitrophenol appears to be 2.5 to 4 times higher than that of young animals. In the newborn rat study of 2,4-dinitrophenol, animals died at 30 mg/kg in the dose-finding study and significant lowering of body and organ weights was observed at 20 mg/kg in the main study. In the 28-day young rat study, clear toxic signs followed by death occurred at 80 mg/kg but there was no definitive toxicity at 20 mg/kg. As unequivocally toxic levels and NOAELs were considered to be 30 and 10 mg/kg/day in newborn rats and 80 and 20 mg/kg/day in young rats, respectively, the toxicity of 2,4-dinitrophenol in newborns again seems to be 2 to 3 times stronger than in young rats. Abnormalities of external development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the toxic response in newborn rats is at most 4 times higher than that in young rats, at least in the cases of 4-nitrophenol and 2,4-dinitrophenol.

Topics: 2,4-Dinitrophenol; Administration, Oral; Animals; Animals, Newborn; Body Weight; Coloring Agents; Dose-Response Relationship, Drug; Female; Kidney; Male; Nitrophenols; No-Observed-Adverse-Effect Level; Organ Size; Organ Specificity; Rats; Rats, Sprague-Dawley; Sex Factors; Time Factors

The present study investigates the influence of long-term ethanol (ETOH) treatment of rats [10% (v/v) for 4, 12, and 36 weeks] on the metabolism of DCM after its oral and inhalative uptake to CO. Biotransformation of DCM to CO as measured by carboxyhemoglobin (COHb) formation was stimulated after long-term ETOH treatment in rats. A single oral dose of DCM (6.2 mmol/kg body mass) caused a significant increase of COHb, the maximum of about 9% occurring approximately 6 hr after DCM administration. In comparison to this control, in the blood of rats pretreated with ETOH (10% v/v) for 4, 12, and 36 weeks COHb values of 18, 17, and 13%, respectively, were measured. Long-term ETOH treatment followed by inhalation of 100, 500, and 2500 ppm DCM for 4 hr stimulated the formation of COHb, compared to controls. The elevation of COHb level was accompanied by decreased concentrations of DCM in the blood. The reason for the elevated biotransformation of DCM was ascertained by means of the determination of p-nitrophenol and aniline hydroxylation in liver microsomes of rats after long-term ETOH treatment to be an increase in cytochrome P450-dependent enzyme activities.

Topics: Aniline Compounds; Animals; Biotransformation; Body Weight; Carbon Monoxide; Carboxyhemoglobin; Carcinogens; Central Nervous System Depressants; Cytochrome P-450 CYP2E1; Drug Administration Schedule; Energy Intake; Ethanol; Liver; Male; Methylene Chloride; Microsomes, Liver; Nitrophenols; Organ Size; Rats; Rats, Wistar; Transferases

1. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. 2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4 mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period. 3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. 4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration. 5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney; Male; Nitrophenols; Organ Size; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Wistar-Shi (genotype +/+), heterozygous Gunn (j/+) and homozygous Gunn (j/j) rats was injected intraperitoneally with 3-methylcholanthrene (3MC) dissolved in corn oil. In rats of all genotypes the hepatic concentration of UDP glucuronosyltransferase (UDPGT) mRNA was increased at 48 and 96 h after the treatment with 3MC. Hepatic activity of 4-nitrophenol UDPGT was increased by 3MC in Wistar-Shi rats and heterozygous Gunn rats but not in homozygous Gunn rats. Urinary ascorbic acid excretion increased 72 and 96 h after the injection with 3MC in Wistar-Shi and heterozygous Gunn rats but not in homozygous Gunn rats. Ninety-six hours after the injection with 3MC, the hepatic concentration of ascorbic acid in Wistar-Shi rats was 90% higher than that in the corresponding control group, whereas in heterozygous and homozygous Gunn rats the increases were 70 and 30%, respectively. Wistar-Shi rats and homozygous Gunn rats were also injected daily for 3 d with sodium phenobarbital. In rats of both genotypes, the activity and hepatic concentration of chloramphenicol-UDPGT mRNA and liver and urine ascorbic acid concentration were increased by sodium phenobarbital. The data indicate that the stimulation of the expression of both the 4-nitrophenol and chloramphenicol UDPGT genes plays a key role in the ascorbic acid biosynthesis induced by 3MC and sodium phenobarbital.

Topics: Analysis of Variance; Animals; Ascorbic Acid; Base Sequence; Blotting, Northern; Body Weight; Chloramphenicol; Gene Expression Regulation, Enzymologic; Glucuronosyltransferase; Injections, Intraperitoneal; Liver; Methylcholanthrene; Molecular Sequence Data; Nitrophenols; Organ Size; Phenobarbital; Polymerase Chain Reaction; Rats; Rats, Gunn; Rats, Inbred Strains; RNA, Messenger; Time Factors; Xenobiotics

The effects of subacute treatment with cocaine on activities of cocaine N-demethylase, UDP-glucuronyltransferase (GT) toward 4-nitrophenol and phenolphthalein and sulfotransferase (ST) toward androsterone and 4-nitrophenol in livers from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated. Hepatic metabolism of cocaine was different between the sexes (with males having higher N-demethylase activity) and the strains (with WKY rats having higher activity). The effects of subacute cocaine administration on the activity of cocaine N-demethylase were also sex- and strain-related. Whereas cocaine administration increased activity of hepatic N-demethylase in both female strains, it decreased activity in male WKY and had no effect on activity in male SHR. Sex and strain-related as well as cocaine-induced differences were also found in activities of hepatic GT toward 4-nitrophenol and phenolphthalein as well as in activity of hepatic ST towards andersterone and 4-nitrophenol. These results suggest that some of the individual variation in the effects of cocaine may be due to sex and genetic differences in the hepatic metabolism of cocaine and/or in sexually and/or/genetically-determined differences in how cocaine affects hepatic metabolism of other xenobiotics.

Topics: Animals; Body Weight; Cocaine; Female; Glucuronosyltransferase; Hypertension; Liver; Male; Nitrophenols; Organ Size; Oxidoreductases, N-Demethylating; Phenolphthalein; Phenolphthaleins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sex Factors; Species Specificity; Sulfurtransferases

N-Nitrosodiethylamine (NEN) and N-nitrodiethylamine (NEA) are carcinogens and in vitro activators of hepatic UDP-glucuronosyltransferase (GT) toward 2-aminophenol (AP) and 4-nitrophenol (NP). In this communication, they were intraperitoneally administered to male Wistar rats for 7 days and GT activities were determined towards AP, NP, phenolphthalein (PH) and testosterone (TS). Administration of 30 or 20 mg/kg dose of NEN caused marked decrease of liver and body weights, and did not affect hepatic GT activities. Injection of 10 mg/kg dose of NEN did not diminish liver and body weights, and increased the maximally activated GT activities toward AP and NP. In contrast, 30 mg/kg dose of NEA, did not affect either liver and body weights or GT activities. N-Nitrosodimethylamine (NMN), which is a carcinogen and a weak in vitro AP GT activator, was more toxic than NEN, and 3.6 mg/kg dose of NMN appears to induce GT toward NP and AP. Administration of 46.5 mg/kg N-nitrosodibutylamine (NBN), which is a carcinogen but not a GT activator, did not affect GT activities or liver body weights.

Topics: Aminophenols; Animals; Body Weight; Diethylamines; Diethylnitrosamine; Dimethylnitrosamine; Glucuronosyltransferase; Injections, Intraperitoneal; Male; Microsomes, Liver; Nitrophenols; Nitrosamines; Organ Size; Rats; Rats, Inbred Strains

Para-Nitrophenol Sodium Salt (PNSP) has relatively low acute inhalation toxicity; the 4-hr Approximate Lethal Concentration in rats is greater than 4.7 mg/l. One subacute study was conducted at 0, 0.34 and 2.47 mg PNSP/l for ten 6-hr exposures. Darker urine, proteinuria and elevated creatinine and SGOT were seen after exposure and were still evident after 14 days recovery. Methemoglobinemia also was seen and was reversible at 0.34 mg/l after 14 days. In addition, exposure to 2.47 mg/l caused elevated erythrocytes, hemoglobin and hematocrit. A second subacute study at 0.03 and 0.13 mg PNSP/l showed reversible methemoglobinemia only at 0.13 mg/l. The repeated dose no-observable effect level was 0.03 mg/l. No compound-related pathologic changes were noted in any of the studies.

Topics: Administration, Inhalation; Animals; Body Weight; Hematologic Tests; Male; Nitrophenols; Organ Size; Rats

SC-37211, an imidazole with antianaerobic activity, was administered po to male rats for 2 weeks at dosages of 20, 60, and 200 mg/kg/day. Histological changes in the thyroid included irregularly shaped follicles and slightly enlarged follicular cells. Serum triiodothyronine (T3) and/or thyroxine (T4) were significantly decreased in treated animals at all dosages; these decreases were not observed following a 2-week recovery period. The half-life of serum [125I]thyroxine was also significantly decreased in rats treated with SC-37211. Morphological changes in the thyroid are likely the result of thyroid-stimulating hormone (TSH) stimulation, a response to decreased serum T3 and T4 concentrations. The decreases in T3 and T4 were not due to decreases in iodide uptake or organification. There were dose-dependent increases in liver weights, liver-to-body weight ratios, and UDPglucuronosyltransferase activity toward p-nitrophenol and T4. Therefore, the decreases in serum T3 and T4 were probably due to an increase in hepatic metabolism rather than to a direct effect of SC-37211 on the thyroid.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Glucuronosyltransferase; Half-Life; Imidazoles; Iodides; Liver; Male; Microscopy, Electron; Nitrophenols; Organ Size; Rats; Rats, Inbred Strains; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Ethylene glycol dimethyl ether (EGdiME), diethylene glycol dimethyl ether (diEGdiME), triethylene glycol dimethyl ether (triEGdiME), diethylene glycol diethyl ether (diEGdiEE), ethylenethiourea (ETU), sodium selenite (SS), dimethyl phthalate (DMP), naphthalene (NAP), or p-nitrophenol (PNP) were administered by gavage for eight consecutive days to female CD-1 mice. Weight loss was insensitive as an index of sublethal adult toxicity and was inadequate for determining a maximum tolerated dose. LD50 values indicate that SS, NAP, and PNP were more toxic (8.4, 353.6, and 625.7 mg/kg, respectively) than the polyglycol ethers, ETU, and DMP (LD50 values ranged from 2525.8 to 6281.9 mg/kg). Each of the compounds was administered on d 7 through 14 to pregnant animals at a single dose estimated to be at or just below the threshold of adult lethality. In such a reproductive study, each of the compounds could be categorized on the basis of the pattern of maternal lethality and fetotoxicity which it produced. The number of dams with complete resorptions was significantly increased after administration of ETU, and no mice in the EGdiME-, diEGdiME-, or triEGdiME-treated groups delivered any viable offspring. Maternal lethality was significant in the EGdiME, triEGdiME, PNP, and NAP groups. There was a slight reduction in the average number of live pups per litter in the diEGdiEE- and PNP-treated groups and a significant reduction in the NAP group. The number dead per litter was increased with diEGdiEE. SS and DMP had no effect on maternal or fetal survival at the doses administered. Individual pup weight at d 1 postpartum was only significantly reduced by diEGdiEE, and no gross congenital abnormalities were detected in neonates from any treatment group. These results provide guidelines for the subsequent toxicity testing of these chemicals.

Topics: Administration, Oral; Analysis of Variance; Animals; Birth Weight; Body Weight; Drug Evaluation, Preclinical; Ethylene Glycols; Ethylenethiourea; Female; Fetal Death; Fetus; Imidazoles; Lethal Dose 50; Maternal-Fetal Exchange; Mice; Naphthalenes; Nitrophenols; Phthalic Acids; Pregnancy; Reproduction; Selenious Acid; Selenium

Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 mM) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.

Topics: Acetaminophen; Aminophenols; Animals; Body Weight; Injections, Intraperitoneal; Kidney Cortex Necrosis; Male; Nitrophenols; Organ Size; Rats; Rats, Inbred F344

Estradiol benzoate (EB), testosterone propionate (TP), progesterone (PG), corticosterone (CS), 3-methylcholanthrene (MC) and phenobarbital (PB) were administered to Wistar rats and their effects on hepatic sulfotransferase (ST) activities toward androsterone (AD) and 4-nitrophenol (NP) were determined. ST activity toward AD was increased by pretreatment with EB and PG in male rats. ST activity toward NP was increased by administration of TP and PG in females, whereas the enzyme activity was suppressed by pretreatment with EB in males. Administration of CS, MC and PB did not significantly affect ST activities toward AD and NP. These results indicate that sex difference in rat liver ST activities appears to be primarily regulated by androgenic, estrogenic and progestational hormones.

Topics: Aging; Androsterone; Animals; Body Weight; Corticosterone; Cytosol; Estradiol; Gonadal Steroid Hormones; Liver; Male; Methylcholanthrene; Nitrophenols; Organ Size; Phenobarbital; Progesterone; Rats; Rats, Inbred Strains; Sulfurtransferases; Testosterone

Young male rats (SD, CD strain) were fed semisynthetic isocaloric diets ad lib for different time periods (3,7,14, or 28 days); both carbohydrate (starch or sucrose) content and fat content were varied. High starch (HST) diet contained starch (73% of calories), corn oil (6%), and casein (21%); low starch (LST) diet contained 6, 73, and 21% of calories, respectively. In high sucrose (HS) or low sucrose (LS) diets, starch was replaced by sucrose. Rats fed LST and LS diets had decreased liver weight compared to those fed HST and HS diets, while liver microsomal protein content (mg/gm liver) was the same in all groups. Significant decreases in microsomal cytochrome P-450 from the basal level were observed in all diets over the period of experimental feeding. This decrease was more prominent with HST or HS diets compared to LST or LS dietary groups. HS diet feeding produced this decrease in cytochrome P-450 levels by 3 days; however, animals on HST diet required 7 days of feeding before they experienced a similar decrease in cytochrome P-450 levels. At 14 days, HST-fed animals had 52% lower liver microsomal cytochrome P-450 than did LST-fed animals. HS-fed animals had 36% lower cytochrome P-450 than LS-fed at 28 days. Similar results were observed for dietary effects on cytochrome b5. Aminopyrine demethylase activity decreased steadily on all diets. p-Nitrophenol glucuronidation was significantly increased in all dietary groups after 2 weeks of diet feeding. These results suggest that dietary carbohydrates and fat (particularly the relative quantities of carbohydrate and fat) may significantly influence the hepatic drug-metabolizing enzymes. It is speculated that these changes may occur due to alteration in the phospholipid composition of endoplasmic reticulum or by limiting the supply of cofactor(s) necessary for optimal mixed function oxidation and conjugation.

Topics: Aminopyrine N-Demethylase; Animals; Body Weight; Cytochrome b Group; Cytochrome P-450 Enzyme System; Cytochromes b5; Dietary Carbohydrates; Food; In Vitro Techniques; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Nitrophenols; Organ Size; Pharmaceutical Preparations; Proteins; Rats; Rats, Inbred Strains; Time Factors

Topics: Aniline Compounds; Animals; Anisoles; Aroclors; Body Weight; DNA; Esterases; Glucuronates; Glutathione; Hexosyltransferases; Liver; Male; Mixed Function Oxygenases; Nitro Compounds; Nitrophenols; Organ Size; Oxidoreductases; Polychlorinated Biphenyls; Proteins; Rats; RNA; Sulfobromophthalein; Time Factors; Uridine Diphosphate Sugars

Topics: Acid Phosphatase; Age Factors; Animals; Body Weight; Cathepsins; Diet; DNA; Leg; Liver; Lysosomes; Muscles; Nitrophenols; Protein Deficiency; Proteins; Rats

Topics: Acid Phosphatase; Amylases; Animals; Body Weight; Cathepsins; Centrifugation, Density Gradient; Edetic Acid; Glycerophosphates; Hydrogen-Ion Concentration; Isoproterenol; Lysosomes; Male; Nitrophenols; Organ Size; Organophosphorus Compounds; Parotid Gland; Rats; Subcellular Fractions; Succinate Dehydrogenase; Time Factors

Topics: Acetates; Animals; Anisoles; Body Weight; Diet; Dose-Response Relationship, Drug; Drug Synergism; Feeding Behavior; Female; Liver; Mercury; Microsomes, Liver; Nitro Compounds; Nitrophenols; Phenobarbital; Phenylphosphonothioic Acid, 2-Ethyl 2-(4-Nitrophenyl) Ester; Rats

Topics: Aniline Compounds; Animal Feed; Animals; Anti-Bacterial Agents; Arsenicals; Bacitracin; Body Weight; Chickens; Food Additives; Intestine, Small; Nitrofurans; Nitrophenols; Organ Size; Seasons; Virginiamycin

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Anisoles; Antifungal Agents; Bilirubin; Body Weight; Chemistry, Agricultural; Glucose-6-Phosphatase; Hepatomegaly; Liver; Male; Methanol; Microsomes, Liver; Nitro Compounds; Nitrophenols; Organ Size; Pyridines; Rats; Stimulation, Chemical

Topics: Adenosine Diphosphate; Animals; Biotransformation; Body Weight; Dehydroepiandrosterone; Dietary Proteins; Edetic Acid; Glucuronates; Liver; Microsomes, Liver; NADP; Nitrophenols; Organ Size; Rats; Subcellular Fractions; Sulfuric Acids; Transferases; Uracil Nucleotides

Topics: Aniline Compounds; Animals; Body Weight; Carbon Tetrachloride; Cytochromes; Glucosephosphate Dehydrogenase; Hexobarbital; Liver; Liver Cirrhosis; NADP; Nitrophenols; Oxidoreductases; Rats; Time Factors

Topics: Animals; Body Weight; Ethers; Female; Fetal Death; Guinea Pigs; Heart; Herbicides; Kidney; Lactation; Lethal Dose 50; Liver; Male; Nitrophenols; Organ Size; Pregnancy; Rabbits; Rats; Reproduction; Spleen; Testis

Topics: Aminopyrine; Animals; Animals, Newborn; Bilirubin; Body Weight; Dealkylation; Erythrocytes; Female; Fetus; Glucuronates; Hexosyltransferases; Humans; Liver; Male; Methylation; Microsomes, Liver; Nitrophenols; Nucleoside Diphosphate Sugars; Organ Size; Oxidoreductases; Protein Biosynthesis; Rats; Sex Factors; Ultrasonics; Uracil Nucleotides; Weaning

Topics: Acetates; Aging; Aniline Compounds; Animals; Animals, Newborn; Bilirubin; Body Weight; Coumarins; Digitalis Glycosides; Enzyme Activation; Female; Glucosamine; Glucuronates; Hexosyltransferases; Kinetics; Liver; Male; Mice; Nitrophenols; Nitrosamines; Nucleoside Diphosphate Sugars; Phenolphthaleins; Phenols; Rats; Saponins; Sex Factors; Spirostans; Surface-Active Agents; Uracil Nucleotides

Topics: Animals; Body Weight; Carbon Tetrachloride Poisoning; Clinical Enzyme Tests; Cytochromes; Enzyme Activation; Hexobarbital; Injections, Subcutaneous; Liver; Liver Cirrhosis, Experimental; Male; Nitrophenols; Organ Size; Phenobarbital; Rats; Time Factors

Topics: Animals; Anisoles; Aorta; Arteriosclerosis; Body Weight; Carbon Isotopes; Cholesterol; Dealkylation; Diet, Atherogenic; Enzyme Activation; Histamine H1 Antagonists; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Nitrophenols; Organ Size; Phenobarbital; Phospholipids; Piperazines; Proteins; Rabbits; Testosterone; Time Factors

Topics: Age Factors; Aminopyrine; Aniline Compounds; Animals; Animals, Newborn; Benzoates; Benzopyrenes; Benzphetamine; Body Weight; Cytochromes; Hexobarbital; Hydrogen-Ion Concentration; In Vitro Techniques; Liver; Microsomes, Liver; Mixed Function Oxygenases; Nitrophenols; Organ Size; Phenytoin; Proteins; Rats

Topics: Animals; Body Weight; DDT; Diet; Enzyme Induction; Liver; Male; Microsomes, Liver; Nitrophenols; Organ Size; Proteins; Rats; Stimulation, Chemical

Topics: Aminopyrine; Aniline Compounds; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Body Weight; Diphenhydramine; Electron Transport; Guinea Pigs; Hexobarbital; Kidney; Liver; Male; Meperidine; Microsomes; NAD; NADP; Nitrobenzenes; Nitrophenols; Organ Size; p-Dimethylaminoazobenzene; Time Factors; Zoxazolamine

Topics: Adjuvants, Anesthesia; Aniline Compounds; Animals; Anisoles; Blood Proteins; Body Weight; Carbon Disulfide; Carbon Isotopes; Cycloheximide; Cytochromes; DNA; Fasting; Heme; Injections, Intraperitoneal; Leucine; Lipids; Liver; Liver Glycogen; Male; Microsomes, Liver; Mixed Function Oxygenases; Nitro Compounds; Nitrophenols; Organ Size; Phenobarbital; Proadifen; Protein Biosynthesis; Proteins; Rats; RNA; Spectrophotometry; Sucrose; Time Factors

Topics: ABO Blood-Group System; Acid Phosphatase; Anemia; Body Weight; Electrophoresis; Erythroblastosis, Fetal; Erythrocytes; Female; Germany, East; Humans; Hyperbilirubinemia; Infant; Infant, Newborn; Infant, Premature; Nitrophenols; Phosphates; Pneumonia; Pregnancy; Starch; Umbilical Cord

Topics: Body Weight; Central Nervous System Agents; Guinea Pigs; Metabolism; Nitrophenols; Oxygen Consumption; Tryptophan

Topics: Animals; Blood Pressure; Blood Pressure Determination; Body Weight; Dinitrophenols; Kidney; Nitrophenols; Rats