Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity

Toxicology and Applied Pharmacology
L M Bornheim

Abstract

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 ...Continue Reading

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Citations

Jul 23, 2002·Journal of Toxicology and Environmental Health. Part a·Ramez LabibMohamed S Abdel-Rahman
Jan 11, 2003·Journal of Toxicology and Environmental Health. Part a·Ramez LabibRita Turkall
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Dec 31, 2020·International Journal of Molecular Sciences·Ewa Galaj, Zheng-Xiong Xi
Jul 10, 2020·Pharmacology, Biochemistry, and Behavior·Larissa Alencar RodriguesAndrea Donatti Gallassi

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