Studies on the acute effects of coumarin and some coumarin derivatives in the rat.
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.
Lake
B G
BG
BIBRA Toxicology International, Carshalton, Surrey, UK.
Evans
J G
JG
Lewis
D F
DF
Price
R J
RJ
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D003374:Coumarins / Q000008:administration & dosage / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D004852:Epoxy Compounds / Q000378:metabolism; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013816:Thermodynamics
D003374:Coumarins; D004852:Epoxy Compounds; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D015660:7-Alkoxycoumarin O-Dealkylase; D005037:Ethylmorphine-N-Demethylase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase