Participation of CYP2A in cocaine-induced hepatotoxicity in female mice.
Female ICR mice were treated with cocaine either alone or in combination with one of several cytochrome P450 (CYP) inducers, i.e. phenobarbital, beta-ionone, dexamethasone and beta-naphthoflavone. Cocaine-induced hepatotoxicity was first observed by pretreatment with phenobarbital, beta-ionone or dexamethasone in accordance with significant elevation of cocaine N-demethylation, the first step of cocaine bioactivation. The hepatic lesions occured in the periportal region (zone 1) by phenobarbital and beta-ionone and in the perivenular region (zone 3) by dexamethasone. The activities of the enzyme specific for CYP isozyme were determined to elucidate the effects of pretreatment with CYP inducers. Beta-naphthoflavone induced CYP1A and 2B but had no effects on hepatotoxicity by cocaine. On the other hand, beta-ionone enhanced hepatotoxicity without induction of CYP3A. Activities of cocaine N-demethylase correlated well with CYP2A (r=0.83) and CYP2B (r=0.81). Cocaine N-demethylation was inhibited particularly by addition of the CYP2A specific inhibitor, 8-methoxypsoralen. Moreover, pretreatment with 8-methoxypsoralen produced a marked inhibition of the hepatotoxicity induced by cocaine in phenobarbital-treated mice. These results suggest that cocaine-induced hepatotoxicity in female mice was mediated in part by CYP2A, participating in cocaine N-demethylation.
Aoki
K
K
School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. kaoki@pharm.showa-u.ac.jp
Takimoto
M
M
Ota
H
H
Yoshida
T
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D003042:Cocaine / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020536:Enzyme Activators / Q000627:therapeutic use*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008107:Liver Diseases / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism; D010634:Phenobarbital / Q000627:therapeutic use; D013250:Steroid Hydroxylases / Q000378:metabolism*
D000927:Anticonvulsants; D020536:Enzyme Activators; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; C054553:cocaine N-demethylase; D000410:Alanine Transaminase; D003042:Cocaine; D010634:Phenobarbital