EFFECT OF CYTOCHROME-P450 INDUCERS ON COCAINE-MEDIATED HEPATOTOXICITY

The effect of several cytochrome P450 (P450) inducers on cocaine metab olism were examined in order to characterize the metabolic events cont ributing to cocaine-induced hepatotoxicity. Phenobarbital (PB)-pretrea tment of mice induced P450s 3A and 2B and markedly increased serum ala nine aminotransferase (ALT) activity after cocaine or norcocaine admin istration. Although dexamethasone (Dex) induced P450s 3A and 2B at lea st to the same extent as PB, no increase in serum ALT activity was obs erved after cocaine or norcocaine administration. Phencyclidine (PCP) pretreatment did not increase either P450s 3A or 2B, yet it markedly e nhanced cocaine- or norcocaine-induced serum ALT activity. In contrast to the marked induction of P450s 3A and 2B, P450 2C was increased onl y 2.5-fold by PB and to an even lesser extent by Dex or PCP, Cannabidi ol (CBD), which inactivates P450s 3A and 2C in mice, completely protec ted mice against cocaine-or norcocaine-induced hepatotoxicity irrespec tive of whether they were induced or not with PB or PCP. Both PB and D ex pretreatment increased the in vitro hepatic microsomal formation of the first two sequential oxidative metabolites of cocaine (norcocaine and N-hydroxynorcocaine), whereas PCP pretreatment did not. Hepatic e sterase activity was also determined after pretreatment with P450 indu cers, since this is the major detoxification pathway in cocaine metabo lism. Dex pretreatment markedly increased (>11-fold) total hepatic est erase activity, whereas PB pretreatment increased it more modestly (le ss than fourfold) and PCP pretreatment had little effect. This marked effect of Dex pretreatment may decrease liver cocaine concentrations a nd thus prefect mice against cocaine-induced hepatotoxicity, despite t heir increased P450 2B and 3A contents. (C) 1998 Academic Press.