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 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

The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives. Male Sprague-Dawley rats were given single ip doses of corn oil (control), coumarin (0.86 and 1.71 mmol/kg body weight), 3,4-dimethylcoumarin (3,4-DMC, 1.71 and 2.57 mmol/kg), 3-, 4- and 6-methylcoumarins (3-MC, 4-MC and 6-MC, 1.71 mmol/kg) and 3- and 4-methyloctahydrocoumarins (3-MOHC and 4-MOHC, 2.57 mmol/kg) and hepatotoxicity assessed after 24 hr. Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, none of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Treatment with coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin O-deethylase activities, whereas one or both mixed-function oxidases appeared to be induced by treatment with 3,4-DMC, 4-MC, 3-MOHC and 4-MOHC. These results provide further evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. That 3- and/or 4-methyl substitution (i.e. 3-MC, 4-MC and 3,4-DMC) leads to a reduction in coumarin-induced hepatotoxicity, due to diminished formation of 3,4-epoxide intermediates, was confirmed by the results of molecular orbital calculations.
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PMID:Studies on the acute effects of coumarin and some coumarin derivatives in the rat. 820 31