Received for publication March 31, 2006.
Revised June 8, 2006.
Accepted for publication June 8, 2006.

In vivo and in vitro characterization of chlorzoxazone metabolism and hepatic CYP2E1 levels in African Green monkeys; induction by chronic nicotine treatment

Abstract

CYP2E1 metabolizes compounds including clinical drugs, organic solvents and tobacco-specific carcinogens. Chlorzoxazone is a probe drug used to phenotype for CYP2E1 activity. Smokers have increased chlorzoxazone clearance during smoking compared with non-smoking periods; however, it is unclear which cigarette smoke component is causing the increased activity. The relationships between in vivo chlorzoxazone disposition, in vitro chlorzoxazone metabolism, and hepatic CYP2E1 have not been investigated in a within-animal design. In control-treated monkeys (Cercopithecus aethiops), the in vivo chlorzoxazone AUC_inf was 19.7 ± 4.5 µgxh/ml, t_1/2 was 0.57 ± 0.07 h and K_el 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 chlorzoxazone disposition, as indicated by a 52% decrease in AUC_inf (p<0.01) and 52% decrease in T_max (p<0.05) compared to control-treated monkeys. The log metabolic ratios at 0.5, 1, 2 and 4 h significantly negatively correlated with chlorzoxazone AUC_inf (p=0.01-0.0001). Monkey hepatic CYP2E1 protein levels significantly correlated with both in vivo AUC_inf (p=0.03) and to in vitro (p=0.004) chlorzoxazone metabolism. Together the data indicated that nicotine induction of in vivo chlorzoxazone disposition is related to the rates of in vitro chlorzoxazone metabolism and to hepatic microsomal CYP2E1 protein levels. Nicotine is one component in cigarette smoke that can increase in vivo chlorzoxazone disposition via induction of hepatic CYP2E1 levels. Thus nicotine exposure may affect the metabolism of CYP2E1 substrates such as acetaminophen, ethanol and benzene.

Key words: CYP induction, CYP2E, cytochrome P450 regulation, drug disposition, enzyme induction, enzyme kinetics, human CYP enzymes, in vivo probes, pharmacokinetics

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