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)

The hepatotoxic effect of carbon tetrachloride (CCl4), reflected by augmented blood aspartate aminotransferase and alanine aminotransferase activities and the extent of histological liver damage, was observed following oral administration of CCl4 to rats. A marked increase of blood transaminase activities and severe degeneration of hepatocytes in the centrilobular region were detected 1-2 days after the administration, while the cytochrome P-450 content and the drug metabolizing activity in livers were depressed immediately after the administration. Based on these results, the effect of CCl4 on hepatic cytochrome P-450 and the histological pattern of liver cells was observed using tissue samples obtained from various liver lobes of rats given CCl4 24 hr previously. Dose-dependent inactivation of cytochrome P-450 by the administration of CCl4 was observed throughout the liver, with the most extensive decrease in the cytochrome content in the median lobe. The extent of liver damage (hydropic swelling degeneration and central necrosis in lobule) was also greater in the median and right liver lobes than in the left lobe. When a small amount of CCl4 was administered, degeneration of liver cells was detected only in the median and right lobes with only slight degeneration in the left lobe. These results indicate different susceptibilities of rat liver lobes to CCl4.
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PMID:Carbon tetrachloride-induced hepatotoxicity in rats: evidence for different susceptibilities of rat liver lobes. 688 48

Ticrynafen, a uricosuric diuretic agent which causes hepatocellular injury in man as an apparent idiosyncratic reaction, was found to impair the function of the isolated perfused rat liver. At concentrations in the perfusate equivalent to those produced in the blood of man by therapeutic doses, the drug led to a striking reduction in bile flow and sulfobromophthalein excretion and release of aspartate aminotransferase into the perfusate. These adverse effects were enhanced by treatment of rats with phenobarbital prior to removal of the liver, indicating that the adverse effect of ticrynafen is probably caused by a metabolite produced in the cytochrome P-450 system.
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PMID:Effects of ticrynafen on hepatic excretory function in the isolated perfused rat liver. 706 19

The effect of carrot extract on carbon tetrachloride (CCl4)-induced acute liver damage was evaluated. The increased serum enzyme levels (viz., glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, sorbitol and glutamate dehydrogenase) by CCl4-induction were significantly lowered due to pretreatment with the extract. The extract also decreased the elevated serum bilirubin and urea content due to CCl4 administration. Increased activities of hepatic 5'-nucleotidase, acid phosphatase, acid ribonuclease and decreased levels of succinic dehydrogenase, glucose-6-phosphatase and cytochrome P-450 produced by CCl4 were reversed by the extract in a dose-responsive way. Results of this study revealed that carrot could afford a significant protective action in the alleviation of CCl4-induced hepatocellular injury.
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PMID:Hepatoprotective activity of carrot (Daucus carota L.) against carbon tetrachloride intoxication in mouse liver. 750 Jun 38

The present research was conducted to evaluate the effect of mitogen pre-exposure on CCl4-induced hepatotoxicity. Male Wistar rats were administered a single i.p. injection of CCl4 (0.3 ml kg-1 in corn oil) 48 h following either a single dose of lead nitrate (0.33 mg kg-1) or distilled water via i.v. injection. Hepatotoxicity, as measured by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was monitored 6, 24, 48, 72 and 120 h after CCl4 exposure. The lead nitrate-pretreated rats displayed markedly lower serum ALT and AST levels at 24, 48 and 72 h than rats pretreated with distilled water. However, treatment with the antimitotic agent colchicine did not alter the lead-induced protection. These findings suggest that the lead-induced protection is not associated with the major mitogenic response of lead, despite its strong temporal association. A critical review of the available toxicological data also argues against the lead protection being a function of its capacity to inhibit cytochrome P-450.
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PMID:Decrease in hepatotoxicity by lead exposure is not explained by its mitogenic response. 778 58

The mechanism of coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of three coumarin derivatives, namely 3,4-dihydrocoumarin (DHC), 3,4-dimethylcoumarin (3,4-DMC) and 6-methylcoumarin (6-MC). Male Sprague-Dawley rats were fed either control diet or diets containing 0.5 or 0.75% coumarin, 0.76% DHC, 0.6 or 0.9% 3,4-DMC or 0.82% 6-MC for 13 wk. The dietary levels of 0.5% coumarin and 0.6% 3,4-DMC, were equimolar (3.43 mmol/100 g diet), as were the dietary levels of 0.75% coumarin, 0.76% DHC, 0.9% 3,4-DMC and 0.82% 6-MC (5.14 mmol/100 g diet). All treatments resulted in an increase in relative liver weight, but only coumarin increased plasma alanine aminotransferase and aspartate aminotransferase activities. Morphological examination of liver sections from coumarin treated rats revealed vacuolation of centrilobular hepatocytes and bile duct hyperplasia. Cholangiofibrosis was also observed, particularly in rats given 0.75% coumarin. Treatment with DHC produced no abnormalities, whereas a slight hypertrophy of centrilobular hepatocytes was observed in some 3,4-DMC treated animals and a slight vacuolation of individual hepatocytes was noted in some 6-MC treated rats. DHC, 6-MC and particularly 3,4-DMC treatment resulted in an induction of cytochrome P-450 dependent mixed function oxidase enzyme activities. All treatments induced hepatic GSHS-transferase and gamma-glutamyltransferase activities, induction being most marked in rats given coumarin and 6-MC. These results provide further evidence that coumarin-induced hepatotoxicity in the rat is due to the formation of a 3,4-epoxide intermediate.
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PMID:Comparison of the hepatic effects of coumarin, 3,4-dimethylcoumarin, dihydrocoumarin and 6-methylcoumarin in the rat. 807 Jul 39

Various reports have described that amino acid substitutions can alter substrate, positional, inhibitory, and target gene specificities of proteins. By using the method of Chou and Fasman, the present work predicts that critical amino acids for converting these substrate specificities of trypsin, L-lactate dehydrogenase, aspartate aminotransferase, beta-lactamase, and cytochrome P-450 are found to exist within regions predicted as beta-turns. The ratios of hydroxylation and oxygenation positions of substrates by cytochrome P-450 and lipoxygenase, respectively, are varied by changes of the protein structures, probably around turn conformations. Inhibitory specificities of bovine pancreatic trypsin inhibitor and alpha 1-antitrypsin and target gene specificity of glucocorticoid receptor are converted by changing turn structures. Occurrence of beta-turn probabilities can be predicted around the amino acid alteration positions of an evolutionally antecedent protein of a nylon degradation enzyme. These findings will have relevance to work on protein engineering and enzyme evolution.
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PMID:Critical amino acids responsible for converting specificities of proteins and for enhancing enzyme evolution are located around beta-turn potentials: data-based prediction. 813 29

Male Sprague-Dawley rats were pretreated with saline, corn oil, sodium phenobarbitone (PB) (100 mg/kg body weight/day), 20-methylcholanthrene (20 MC) (20 mg/kg body weight/day) or Aroclor 1254 (ARO) (100 mg/kg body weight/day) by daily ip injections for 5 days. Animals were then given single oral doses of either 250 or 500 mg coumarin/kg body weight and hepatotoxicity was assessed after 24 hr. Coumarin produced hepatotoxicity, which comprised hepatocyte necrosis and elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, in all pretreated groups. Hepatic microsomal cytochrome P-450 levels were reduced after coumarin administration. In rats pretreated with saline, corn oil or PB, coumarin produced centrilobular hepatic necrosis, whereas in rats pretreated with 20 MC or ARO, coumarin produced periportal hepatic necrosis. These results demonstrate that mixed-function oxidase enzyme inducers can modulate acute coumarin-induced hepatotoxicity in the rat. As coumarin is known to be bioactivated by cytochrome P-450-dependent enzymes, the change in the lobular distribution of toxicity after pretreatment with 20 MC or ARO is presumably due to the induction of particular cytochrome P-450 isoenzymes in periportal hepatocytes.
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PMID:Effect of pretreatment with some mixed-function oxidase enzyme inducers on the acute hepatotoxicity of coumarin in the rat. 828 80

The effects of anabolic-androgenic steroid administration and exercise training on various aspects of hepatic function were investigated in sedentary and trained (treadmill for 12 wk) male and female rats treated orally with fluoxymesterone or methylandrostanolone (2 mg.kg-1 body weight, 5 d.wk-1 for 8 wk). The mean values of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, and total- and high-density lipoprotein-cholesterol remained within normal range in all groups of male animals. The same is true for female rats, except for an increase in alkaline phosphatase activity in the steroid-treated groups. Hepatic microsomal aniline p-hydroxylase activity was reduced in male and increased in female rats by either steroid, whereas no significant effect was detected on 7-ethoxycoumarin deethylase activity. The levels of cytochrome P-450 and cytochrome b5 were markedly decreased by the anabolic-androgenic steroid treatment in male rat microsomes, but neither the steroid administration nor exercise training induced significant changes in the cytochrome levels of female rat livers. Taking into account the significant increase in microsomal protein yield elicited by fluoxymesterone or methylandrostanolone treatment both in males and females, it is noteworthy that the total monooxygenase activities and cytochrome P-450 content, expressed on a per gram liver basis, were significantly increased in female whereas they were apparently unchanged in male rats. In conclusion, the present data show that the prolonged ingestion of high doses of anabolic-androgenic steroids, either with or without concurrent exercise training, can modify in a sex-dependent manner the capacity of rat liver to metabolize drugs without affecting classical serum indicators of hepatic function.
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PMID:Effect of training and anabolic-androgenic steroids on drug metabolism in rat liver. 835 Jul 4

This study assessed effects of exposure to p-xylene, a ubiquitous air pollutant, on mice infected with murine cytomegalovirus (MCMV), a mouse model for a common human virus. It was postulated that adverse health effects could occur as a result of (1) enhanced infection due to xylene-induced immune suppression, (2) increased p-xylene toxicity due to viral suppression of cytochrome P-450 (P-450), and/or (3) additive or synergistic effects on liver function due to tissue injury by both p-xylene and MCMV. Mice were exposed to filtered air, 600 or 1200 ppm p-xylene 6 h/d for 4 d and infected with a sublethal dose of MCMV after the first exposure. No deaths occurred among uninfected, p-xylene-exposed mice or infected, air-exposed mice; 34% and 0% mortality occurred respectively in infected mice exposed to 1200 and 600 ppm p-xylene. Virus titers in the liver and splenic natural killer cell activity were unaffected by exposure to 1200 ppm p-xylene. Small but significant increases in serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities, indicators of liver damage, were observed at 4 d postinfection. p-Xylene exposure had no effect on these serum enzyme activities in uninfected mice, but 1200 ppm potentiated this effect in infected mice. MCMV significantly suppressed and p-xylene significantly increased total P-450 levels in the liver, but there was no significant interaction between the two. Isozymes 1A1, 2B1/B2, and 2E1 were decreased to a similar degree, suggesting that the virus does not target specific isozymes. Enhanced mortality was not due to immune suppression. While p-xylene potentiated liver damage was caused by the virus, the magnitude of serum enzyme activities indicates that this damage was not a likely cause of death. The cause of deaths is unclear, results were consistent with the hypothesis that enhanced mortality was related to enhanced xylene toxicity due to suppression of P-450, although additive or synergistic damage to tissues other than liver cannot be ruled out.
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PMID:Enhanced mortality and liver damage in virus-infected mice exposed to p-xylene. 839 6

The contribution of testosterone to the nephrotoxic effects of 1,2-dichloropropane (DCP) was assessed by a series of castration and sex hormone replacement experiments on Wistar rats. The nephrotoxic action of DCP was evaluated by measuring the accumulation of organic anion and release of aspartate aminotransferase into the incubation medium using a renal cortical slice model. Our data show that sex, castration, and testosterone pretreatment are factors that influence the effect of DCP on renal cortical slices of rats Males appear to be more sensitive to nephrotoxic effects of DCP than females, male castration prevents the nephrotoxic effects of DCP, and pretreatment of females and castrated males with testosterone increases the susceptibility to DCP. In this study an attempt was made to evaluate the role of sex differences in the expression of enzymes participating in Phase I and Phase II detoxication reactions in order to explain the differences in sensitivity of the two genders to the nephrotoxic action of DCP. Our results implicate gender-specific expression of cytochrome P-450 in the kidneys as a predominant factor that determines the different susceptibilities of male and female rats to the nephrotoxic effect of DCP. We propose that the oxidation of DCP by CYP IIE1 is the first saturable and limiting step in the metabolic activation of DCP to nephrotoxic metabolites. It appears that, despite the fact that the nephrotoxic effect of DCP is determined mainly by its cysteine-conjugated metabolites, gluthathione (GSH) content and glutathione S-transferase (GST) activity in kidney are not directly related to increased androgen-related susceptibility to DCP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of sex-related differences in nephrotoxicity of 1.2-dichloropropane in rats. 857 Aug 64


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