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In Vivo and in Vitro Characterization of Chlorzoxazone Metabolism and Hepatic CYP2E1 Levels in African Green Monkeys: Induction by Chronic Nicotine Treatment

The Centre for Addiction and Mental Health, and the Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

CYP2E1 metabolizes compounds, including clinical drugs, organic solvents, and tobacco-specific carcinogens. Chlorzoxazone (CZN) is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased CZN clearance during smoking compared with nonsmoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo CZN disposition, in vitro CZN metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo CZN area under the curve extrapolated to infinity (AUC_inf) was 19.7 ± 4.5 µg µ h/ml, t_1/2 was 0.57 ± 0.07 h, and terminal disposition rate constant calculated from last three to four points on the log-linear end of the concentration versus time curve was 1.2 ± 0.2 /h. In vitro, the apparent V_max was 3.48 ± 0.02 pmol/min/µg microsomal protein, and the K_m was 95.4 ± 1.8 µM. Chronic nicotine treatment increased in vivo CZN disposition, as indicated by a 52% decrease in AUC_inf (p < 0.01) and 52% decrease in T_max (p < 0.05) compared with control-treated monkeys. The log metabolic ratios at 0.5, 1, 2, and 4 h significantly negatively correlated with CZN AUC_inf (p = 0.01–0.0001). Monkey hepatic CYP2E1 levels significantly correlated with both in vivo AUC_inf (p = 0.03) and in vitro (p = 0.004) CZN metabolism. Together, the data indicated that nicotine induction of in vivo CZN disposition is related to the rates of in vitro CZN metabolism and hepatic microsomal CYP2E1 protein levels. Nicotine is one component in cigarette smoke that can increase in vivo CZN metabolism via induction of hepatic CYP2E1 levels. Thus, nicotine exposure may affect the metabolism of CYP2E1 substrates such as acetaminophen, ethanol, and benzene.

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