Participation of CYP2A in cocaine-induced hepatotoxicity in female mice

Female ICR mice were treated with cocaine either alone or in combination wi th one of several cytochrome P450 (CYP) inducers, i.e. phenobarbital, beta- ionone, dexamethasone and beta-naphthoflavone. Cocaine-induced hepatotoxici ty was first observed by pretreatment with phenobarbital, beta-ionone or de xamethasone in accordance with significant elevation of cocaine N-demethyla tion, the first step of cocaine bioactivation. The hepatic lesions occured in the periportal region (zone 1) by phenobarbital and beta-ionone and in t he perivenular region (zone 3) by dexamethasone. The activities of the enzy me specific for CW isozyme were determined to elucidate the effects of pret reatment with CYP inducers. beta-Naphthoflavone induced CYP1A and 2B but ha d no effects on hepatotoxicity by cocaine. On the other hand, beta-ionone e nhanced hepatotoxicity without induction of CYP3A. Activities of cocaine N- demethylase correlated well with CYP2A (r = 0.83) and CYP2B (r = 0.81). Coc aine N-demethylation was inhibited particularly by addition of the CYP2A sp ecific inhibitor, 8-methoxypsoralen. Moreover, pretreatment with 8-methoxyp soralen produced a marked inhibition of the hepatotoxicity induced by cocai ne in phenobarbital-treated mice. These results suggest that cocaine-induce d hepatotoxicity in female mice was mediated in part by CYP2A, participatin g in cocaine N-demethylation.