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

Lee, AM; Yue, Jiang; Tyndale, Rachel F.

doi:10.1124/dmd.106.010363

Cited by 20 publications

(18 citation statements)

References 38 publications

(62 reference statements)

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“…Also, a study with 21-day nicotine dosing in African green monkeys demonstrated the induction of hepatic CYP2E1 protein and activity, including increased chlorzoxazone metabolism in vivo [33]. Moreover, nicotine treatment increased markedly CYP2E1 protein as studied with immunocytochemistry in a human neuroblastoma cell line IMR-32 [16].…”

Section: Discussionmentioning

confidence: 99%

Effects of nicotine on cytochrome P450 2A6 and 2E1 activities

Hukkanen

Jacob

Peng

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone.• Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity.• The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS• This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing.• High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates.• The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMSSmoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODSThe study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTSThere was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference -9.7, -0.6, P = 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONSCYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown.

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Section: Discussionmentioning

confidence: 99%

Effects of nicotine on cytochrome P450 2A6 and 2E1 activities

Hukkanen

Jacob

Peng

et al. 2010

Brit J Clinical Pharma

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“…Plasma CZN levels were assayed on the basis of the methods in Lee et al (2006b). In brief, plasma was centrifuged at 3000g for 10 min, after which 100 l of the supernatant was removed and incubated with ␤-glucuronidase (10 mg/ml, 50 l) overnight at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Ethanol is an inducer of hepatic CYP2E1 protein and activity in humans and monkeys (Lieber, 1997;Ivester et al, 2007). Smoking increases CYP2E1 activity in humans (Benowitz et al, 2003), and chronic nicotine treatment increases hepatic CYP2E1 protein levels and activity in monkeys (Lee et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

“…The African green monkey (AGM) has been established as an excellent animal model of human CYP2E1 expression and activity (Lee et al, 2006b). Chlorzoxazone (CZN), a clinically used muscle relaxant that is metabolized by CYP2E1 to 6-hydroxychlorzoxazone (6OHCZN), is a validated probe drug for the measurement of CYP2E1 activity in both humans and monkeys (Ernstgård et al, 2004;Lee et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

“…Chlorzoxazone (CZN), a clinically used muscle relaxant that is metabolized by CYP2E1 to 6-hydroxychlorzoxazone (6OHCZN), is a validated probe drug for the measurement of CYP2E1 activity in both humans and monkeys (Ernstgård et al, 2004;Lee et al, 2006b). As in other species, CZN 6-hydroylation in monkey liver microsomes can be inhibited by anti-CYP2E1 antibodies and selective chemical inhibitors of CYP2E1, providing evidence that CYP2E1 is the primary enzyme involved in the 6-hydroxylation of CZN (Amato et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Independent and Combined Effects of Ethanol Self-Administration and Nicotine Treatment on Hepatic CYP2E1 in African Green Monkeys

Ferguson

Miksys²,

Palmour³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 2E1 metabolizes ethanol and also bioactivates many toxins and procarcinogens. Elevated levels of hepatic CYP2E1 are associated with an increased susceptibility to chemical toxicity and carcinogenesis. This study investigated the induction of hepatic CYP2E1 by ethanol and nicotine, alone and in combination, in a nonhuman primate model. Monkeys that selfadministered ethanol and that received subcutaneous injections of nicotine (0.5 mg/kg b.i.d.), alone and in combination, were compared with control animals (four groups, n ‫؍‬ 10/group). Chlorzoxazone (CZN) was used as a probe drug to phenotype in vivo CYP2E1 activity before and after chronic ethanol and/or nicotine exposure. CYP2E1 protein levels and in vitro chlorzoxazone metabolism were assessed in liver microsomes. Average daily ethanol consumption was Ϸ3.0 g/kg (blood ethanol levels Ϸ24 mM) and was unaffected by nicotine treatment. Ethanol self-administration and nicotine treatment, alone and in combination, significantly increased in vivo CZN disposition compared with that in control animals. The effect of ethanol was only observed at higher levels of intake. Ethanol and nicotine increased CYP2E1 protein levels and in vitro CZN metabolism, with combined exposure to both drugs resulting in the greatest increase. The effect of ethanol was also dependent on level of intake. Chronic exposure to ethanol and nicotine induced hepatic CYP2E1 activity and protein levels, particularly when both drugs were used in combination and when ethanol intake was high. These results have important implications for public health, given the association between elevated CYP2E1 and disease, and the large proportion of individuals who are exposed to ethanol and nicotine, often in combination.

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Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Dey

2013

Subcellular Biochemistry

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Research on Cytochrome P450 2E1 (CYP2E1), a key enzyme in alcohol metabolism has been very well documented in literature. Besides the involvement of CYP2E1 in alcohol metabolism as illustrated through the studies discussed in the chapter, recent studies have thrown light on several other aspects of CYP2E1 i.e. its extrahepatic expression, its involvement in several diseases and pathophysiological conditions; and CYP2E1 mediated carcinogenesis and modulation of drug efficacy. Studies involving these interesting facets of CYP2E1 have been discussed in the chapter focusing on the recent observations or ongoing studies illustrating the crucial role of CYP2E1 in disease development and drug metabolism.

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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

Cited by 20 publications

References 38 publications

Effects of nicotine on cytochrome P450 2A6 and 2E1 activities

Effects of nicotine on cytochrome P450 2A6 and 2E1 activities

Independent and Combined Effects of Ethanol Self-Administration and Nicotine Treatment on Hepatic CYP2E1 in African Green Monkeys

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

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