Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Susceptible rat strains develop hepatobiliary injury following the surgical creation of self-filling blind loops that cause small bowel bacterial overgrowth. Luminal bacteria or their cell wall polymers were implicated in the pathogenesis of the lesions because sham-operated rats and rats with self-emptying blind loops, having only slightly increased bacterial counts, did not develop hepatic injury. In this study, antibiotics with different spectra of activities were continuously administered starting 1 day or 22 days after surgery to determine which intestinal flora may be responsible for the development of hepatic injury in rats with small bowel bacterial overgrowth. Four weeks following surgery, Lewis rats with self-filling blind loops receiving no antibiotics had elevated liver histology scores (8.2 +/- 1.3 vs. 0.7 +/- 0.4) and plasma aspartate aminotransferase levels (269 +/- 171 vs. 84 +/- 24) compared with sham-operated rats, P less than 0.001. Oral gentamicin as well as oral and intraperitoneal polymyxin B, which binds endotoxin, did not prevent hepatic injury in rats with self-filling blind loops. However, oral metronidazole and tetracycline therapy continuously administered beginning 1 day after surgery diminished hepatic injury (histology score 3.0 +/- 1.8, 2.9 +/- 1.1; aspartate aminotransferase 87 +/- 25, 98 +/- 34; respectively P less than 0.001 compared with self-filling blind loops receiving no antibiotics). Metronidazole also protected Wistar rats that require 12 weeks to develop hepatic injury following experimentally induced small bowel bacterial overgrowth compared with rats with self-filling blind loops that received no antibiotic treatment (histology score 10.4 +/- 1.3 vs. 0.7 +/- 1.1, and aspartate aminotransferase 273 +/- 239 vs. 76 +/- 20, P less than 0.001). When rats started metronidazole therapy 22 days after self-filling blind loop surgery, elevated aspartate aminotransferase values decreased to normal during the next 77 days and final histology scores were normal. All rats with self-filling blind loops had negative peritoneal, liver, spleen, and blood cultures but approximately 75% of mesenteric lymph node cultures were positive irrespective of antibiotic treatment. Because Bacteroides species have been implicated in causing vitamin B12 and disaccharidase deficiencies in rats with self-filling blind loops, we documented the presence or absence of these organisms from blind loops using selective culture techniques. Metronidazole and tetracycline eliminated Bacteroides sp. from blind loops, but polymyxin B and gentamicin did not.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. 198 47

The effect of phenobarbital (100 mg/kg i.p.) and 6-aminonicotinamide (6AN) (35 mg/kg i.p.) on enzyme activities related to energy transduction was investigated on the homogenate "in toto", non-synaptic mitochondrial fraction and synaptosomal fraction isolated from different rat brain areas (cerebral cortex, hippocampus, hypothalamus, striatum, and medulla oblongata). 6AN treatment decreased: phosphofructokinase in all the areas tested; lactate dehydrogenase on the homogenate "in toto" in striatum and hypothalamus, and on the synaptosomal fraction in cerebral cortex and corpus striatum; succinate dehydrogenase on non-synaptic mitochondrial fraction in hippocampus and striatum. Finally, aspartate aminotransferase was increased on non-synaptic mitochondrial fraction in striatum and medulla oblongata. Phenobarbital treatment induced an increase of total NADH cytochrome c reductase on mitochondrial fraction in hippocampus and hypothalamus, and a decrease of cytochrome oxidase activity on non-synaptic mitochondrial fraction in hypothalamus and medulla oblongata.
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PMID:Phenobarbital and 6-aminonicotinamide effect on cerebral enzymatic activities related to energy metabolism in different rat brain areas. 303 30

The ability of trichloroethylene (TCE) and selected metabolites to induce single-strand breaks in hepatic DNA of male B6C3F1 mice and Sprague-Dawley rats in vivo was evaluated using an alkaline unwinding assay. Doses of TCE of 22-30 mmol/kg were required to produce strand breaks in DNA in rats, whereas a dose of 11.4 mmol/kg was sufficient to increase the rate of alkaline unwinding in mice. To assess the importance of TCE metabolism to this response, rats were subjected to pretreatments of ethanol, phenobarbital, TCE, or the appropriate vehicle for 4 days prior to challenge doses of TCE. Phenobarbital and TCE, but not ethanol pretreatments, reduced the dose of TCE required to produce significant increases in single-strand breaks. In another series of experiments, mice and rats were treated with metabolites of TCE. Trichloroacetate, dichloroacetate, and chloral hydrate induced strand breaks in hepatic DNA in a dose-dependent manner in both species. Strand breaks in DNA were observed at doses that produced no observable hepatotoxic effects as measured by serum aspartate aminotransferase and alanine aminotransferase levels. The slopes of the dose-response curves and the order of potency of these metabolites differed significantly between rats and mice, suggesting that different mechanisms of single-strand break induction may be involved in the two species. These data provide a potential explanation for the different sensitivity of mice and rats to the hepatocarcinogenic effects of TCE.
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PMID:Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo. 337 13

An experimental animal model designed specifically to simulate liver fibrosis and cirrhosis in childhood is described. Phenobarbitone was administered continuously from the 4th day of life and carbon tetrachloride intermittently from the 13th day to developing rats for 10 weeks. Treated animals showed hepatic necrosis, hepatic regeneration and a progressive increase in hepatic fibrosis; cirrhosis developed before the animals reached sexual maturity at 72 days or were fully grown. Hepatic prolyl hydroxylase activity increased to a maximum level after 20 days of treatment, before increased hepatic collagen could be detected, and fell to a lower level as cirrhosis became established. Serum activities of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase gave a similar pattern, a marked increase at 20 days of age followed by a fall to near normal levels as hepatic damage became more severe. By the 26th day of life hepatic collagen levels were increased significantly and rose thereafter progressively as fibrosis became more widespread throughout the liver. Cirrhosis developed between the 38th and 75th days. Cirrhosis remained 10 weeks after discontinuation of treatment with phenobarbitone and carbon tetrachloride treatment.
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PMID:Carbon tetrachloride-induced hepatic fibrosis and cirrhosis in the developing rat: an experimental model of cirrhosis in childhood. 630 21

The ability of phenobarbital to induce the expression and activity of microsomal drug monooxygenases in the liver presents one of the most important issues in the field of chemical interactions and in the toxicity of xenobiotics. The model of rat liver injury induced by a single dose of thioacetamide (500 mg/kg intraperitoneally) was used to study the effect of phenobarbital (80 mg/kg/day intraperitoneally) for 5 days prior to thioacetamide. Serum parameters of liver injury such as aspartate aminotransferase activity, gamma-glutamyl transferase activity and the total bilirubin levels, as well as the activities of hepatic FAD and cytochrome P450 microsomal monooxygenases, were assayed in 2- and 12-month-old rats. Samples of blood and liver were obtained from controls (injected at 0 h with 0.5 ml of 0.9% NaCl) and at 12, 24, 48, 72 and 96 h of thioacetamide intoxication either to non-treated or phenobarbital pretreated rats. Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatment was demonstrated at morphological level, and by significant increases in the activities of serum aspartate aminotransferase and gamma-glutamyl transferase, and in the levels of total bilirubin. The extent of potentiation of thioacetamide-induced liver injury by phenobarbital pretreatment was similar in both age groups. Microsomal FAD monooxygenase activity, the enzyme responsible for thioacetamide biotransformation, was significantly enhanced (twofold) by phenobarbital pretreatment, and also underwent a further increase following thioacetamide, preceding the peak of necrosis. Cytochrome P450 monooxygenases were induced by phenobarbital pretreatment more than sixfold, and sharply decreased when phenobarbital was withdrawn and thioacetamide administered, showing at 48 h intoxication values close to basal. Phenobarbital pretreatment potentiated thioacetamide necrogenicity, and this potentiation was parallel to the induction of the microsomal FAD monooxygenase system, both by phenobarbital and by thioacetamide itself. The extent of thioacetamide-induced liver injury was significantly higher in 12-month-old rats, but the effect of phenobarbital pretreatment was similar in both age groups.
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PMID:Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatment in rats. Inducibility of FAD monooxygenase system and age effect. 1067 Aug 21

Long-term administration of phenobarbital has been reported to cause hepatic injury in dogs. Phenobarbital induces hepatic enzymes, and it may be difficult to distinguish the effect of enzyme induction on serum liver enzyme activities from actual hepatic damage. The hepatotoxicity of phenobarbital and the impact of enzyme induction on serum liver enzyme activity were investigated prospectively in 12 normal dogs. Phenobarbital was administered for 29 weeks at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h, resulting in therapeutic serum phenobarbital concentrations (20-40 microg/mL). Serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), fasted bile acids (fBA), total bilirubin, and albumin were determined before and during treatment. Lateral abdominal radiographs, abdominal ultrasounds, and histopathologic examinations of liver tissue obtained by ultrasound-guided biopsy were performed before and during treatment. Radiographs revealed a moderate increase in liver size in most dogs. Ultrasonographic examination revealed no change in liver echogenicity or architecture. No evidence of morphologic liver damage was observed histopathologically. ALP and ALT increased significantly (P < .05), GGT increased transiently, and albumin decreased transiently during the study. There were no significant changes in AST, bilirubin, and fBA. These results suggest that increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and bilirubin, and ultrasonographic evaluation of the liver are not affected by the enzyme-inducing effect of phenobarbital and can therefore be helpful to assess liver disease in dogs treated with the drug.
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PMID:Effects of long-term phenobarbital treatment on the liver in dogs. 1077 88

The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1-dichloro-2,2-difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1/2 were induced by beta-naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications. Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of gamma-glutamyltranspeptidase (gamma GT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N-acetyl-beta-D-glucosaminidase (NAG) in 24-h urine were increased similarly, but urinary excretion of glucose, proteins and beta2-microglobulin (beta2-m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE- and DCDFE-exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure. Beta-naphthoflavone-pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism.
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PMID:Effect of beta-naphthoflavone and phenobarbital on the nephrotoxicity of chlorotrifluoroethylene and 1,1-dichloro-2,2-difluoroethylene in the rat. 1574 58

Flunitrazepam (FNZ) is a benzodiazepine derivative more potent than diazepam. FNZ abuse in the US has emerged in the last few years and has a growing popularity among young people and drug abusing populations. Ethanol (EtOH) consumption with FNZ enhances euphoria and onset of action. It is postulated that FNZ and EtOH cause liver cell injury. In this study, hepatocytes are employed to study the hepatotoxicity of FNZ, EtOH and their combination (FNZ-EtOH). Hepatocytes (2x10(6) cells/ml) isolated from male Sprague-Dawley rats were exposed to saline, FNZ, EtOH or FNZ-EtOH in combination. The uptake of 0.4% trypan blue and the leakage of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes into the incubation media were used to assess cell membrane damage of hepatocytes. Where metabolism of FNZ is nearly complete through several hepatic pathways, animal pretreatment with Phenobarbital was used to study the effect of microsomal enzyme induction on cellular injury. FNZ (0.16mm), EtOH (32.56mm) or their combination caused a significant (P<0.05) decrease in cell viability. Compared with control, FNZ and FNZ-EtOH in combination caused significant AST leakage over the 2-hour incubation period. EtOH alone caused significant AST leakage after 2 hours of incubation. The leakage of ALT enzyme was significant for FNZ, EtOH and FNZ-EtOH over the 2-hour incubation period. While FNZ alone did not produce any significant enzymatic leakage in the Phenobarbital pretreated groups, the leakage of ALT and AST were significant for FNZ-EtOH in combination as early as 30 minutes of incubation. A significant depletion (P<0.05) of glutathione (GSH) was observed for EtOH and FNZ-EtOH in combination treated samples. This investigation suggests that FNZ and EtOH cause hepatotoxicity, and their combinations have an additive effect in increasing liver toxicity. Induction of microsomal enzymes revealed that FNZ is more hepatotoxic than the metabolites. And FNZ alone has no effect on GSH content.
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PMID:Hepatotoxicity of flunitrazepam and alcohol in vitro. 2065 96