Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity.
The effect of several cytochrome P450 (P450) inducers on cocaine metabolism were examined in order to characterize the metabolic events contributing to cocaine-induced hepatotoxicity. Phenobarbital (PB)-pretreatment of mice induced P450s 3A and 2B and markedly increased serum alanine aminotransferase (ALT) activity after cocaine or norcocaine administration. Although dexamethasone (Dex) induced P450s 3A and 2B at least to the same extent as PB, no increase in serum ALT activity was observed after cocaine or norcocaine administration. Phencyclidine (PCP) pretreatment did not increase either P450s 3A or 2B, yet it markedly enhanced cocaine- or norcocaine-induced serum ALT activity. In contrast to the marked induction of P450s 3A and 2B, P450 2C was increased only 2.5-fold by PB and to an even lesser extent by Dex or PCP. Cannabidiol (CBD), which inactivates P450s 3A and 2C in mice, completely protected mice against cocaine- or norcocaine-induced hepatotoxicity irrespective of whether they were induced or not with PB or PCP. Both PB and Dex 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 esterase activity was also determined after pretreatment with P450 inducers, since this is the major detoxification pathway in cocaine metabolism. Dex pretreatment markedly increased (> 11-fold) total hepatic esterase activity, whereas PB pretreatment increased it more modestly (less than fourfold) and PCP pretreatment had little effect. This marked effect of Dex pretreatment may decrease liver cocaine concentrations and thus protect mice against cocaine-induced hepatotoxicity, despite their increased P450 2B and 3A contents.
Bornheim
L M
LM
Department of Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0450, USA. lmb@itsa.vcsf.edu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009294:Narcotics / Q000493:pharmacokinetics / Q000633:toxicity*; D010622:Phencyclidine / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018691:Excitatory Amino Acid Antagonists; D006993:Hypnotics and Sedatives; D007527:Isoenzymes; D009294:Narcotics; C008671:norcocaine; C036718:8-hydroxynorcocaine; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine; D010622:Phencyclidine; D010634:Phenobarbital