Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Yue, Jiang; Khokhar, Jibran Y.; Miksys, Sharon; Tyndale, Rachel F.

doi:10.1016/j.ejphar.2009.03.015

Cited by 28 publications

(22 citation statements)

References 63 publications

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“…It was previously shown that rats exposed to both ethanol and nicotine had significantly greater levels of hepatic CYP2E1 protein compared with rats exposed to either drug alone (Yue et al, 2009). This enhancement of CYP2E1 protein was partially attributed to a nicotine-stimulated increase in ethanol consumption.…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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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“…The induction of CYP2E1 protein in the brain of smoking alcoholics in comparison with nonalcoholic nonsmokers has been proposed [16]. Several studies with experimental animals have shown the induction of CYP2E1 protein and activity in liver and brain by nicotine administration [17][18][19][20]. Furthermore, nicotine treatment increased CYP2E1 protein in a human neuroblastoma cell line [16].…”

Section: Introductionmentioning

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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“…CYP2E1 is increased 1.7, 1.8, and 1.4 fold by the three doses of nicotine alone; CYP2E1 levels are increased by voluntary ethanol intake alone and a further 2.4, 2.2, and 1.8 fold by 0.4, 0.8, and 1.2 mg/kg nicotine respectively versus saline pretreatment (Yue et al 2009 ) . CYP2E1 level correlates with alcohol consumption on day 10 (Yue et al 2009 ) . Chronic nicotine increases voluntary ethanol intake thereby enhancing CYP2E1 level (Yue et al 2009 ) .…”

Section: Rf Tyndale Synergistic Induction Of Cyp2e1 By Ethanol and mentioning

confidence: 97%

“…Nicotine pretreatment of rats increases voluntary ethanol intake on day 10 compared to saline pretreatment (Yue et al 2009 ) . CYP2E1 is increased 1.7, 1.8, and 1.4 fold by the three doses of nicotine alone; CYP2E1 levels are increased by voluntary ethanol intake alone and a further 2.4, 2.2, and 1.8 fold by 0.4, 0.8, and 1.2 mg/kg nicotine respectively versus saline pretreatment (Yue et al 2009 ) .…”

Section: Rf Tyndale Synergistic Induction Of Cyp2e1 By Ethanol and mentioning

confidence: 98%

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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Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Cited by 28 publications

References 63 publications

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

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

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

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

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