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.