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Research ArticleArticle

Down-Regulation of Hepatic Nicotine Metabolism and a CYP2A6-Like Enzyme in African Green Monkeys after Long-Term Nicotine Administration

Kerri A. Schoedel, Edward M. Sellers, Roberta Palmour and Rachel F. Tyndale
Molecular Pharmacology January 2003, 63 (1) 96-104; DOI: https://doi.org/10.1124/mol.63.1.96
Kerri A. Schoedel
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Edward M. Sellers
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Roberta Palmour
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Rachel F. Tyndale
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Abstract

Nicotine metabolism is decreased in smokers compared with nonsmokers, but the mechanism(s) responsible for the slower metabolism are unknown. Nicotine is inactivated to cotinine by CYP2A6 in human liver [nicotine C-oxidation (NCO)]. CYP2B6 also metabolizes nicotine to cotinine but with lower affinity than CYP2A6. To evaluate the effects of long-term nicotine treatment on hepatic levels of CYP2A6 and CYP2B6, and nicotine metabolism, an African green monkey (AGM) model was developed. As in humans, approximately 80 to 90% of in vitro hepatic NCO is mediated by a CYP2A6-like protein (CYP2A6agm) in this species, as determined by inhibition studies. Male AGM (n = 6 per group) were treated for 3 weeks with nicotine (s.c., 0.3 mg/kg, b.i.d.), phenobarbital (oral, 20 mg/kg, as a positive control for P450 induction), and/or saline (s.c., b.i.d.). Immunoblotting demonstrated a 59% decrease (p < 0.05) in hepatic CYP2A6agm protein in nicotine-treated animals. A CYP2B6-like protein (CYP2B6agm) was modestly and insignificantly decreased (14%, p = 0.11). In vitro NCO was decreased by 41% in the nicotine-treated group (p < 0.05), mediated by a decrease in CYP2A6agm, as demonstrated using inhibitory antibodies. CYP2A6agm mRNA (33%,P ≤ 0.05) and CYP2B6agm (35%,p < 0.01) mRNA were also significantly decreased in the nicotine-treated group. Phenobarbital-treated animals demonstrated an increase in CYP2B6agm (650%, p < 0.001), but not CYP2A6agm (20%, p = 0.49). NCO was increased in the phenobarbital-treated group (55%,p < 0.05) by an increase in CYP2B6agm-mediated NCO. Consistent with the slower nicotine metabolism observed in smokers, nicotine may decrease its own metabolism in primates by decreasing the expression of the primary nicotine-metabolizing enzyme CYP2A6.

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Molecular Pharmacology: 63 (1)
Molecular Pharmacology
Vol. 63, Issue 1
1 Jan 2003
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Research ArticleArticle

Down-Regulation of Hepatic Nicotine Metabolism and a CYP2A6-Like Enzyme in African Green Monkeys after Long-Term Nicotine Administration

Kerri A. Schoedel, Edward M. Sellers, Roberta Palmour and Rachel F. Tyndale
Molecular Pharmacology January 1, 2003, 63 (1) 96-104; DOI: https://doi.org/10.1124/mol.63.1.96

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Research ArticleArticle

Down-Regulation of Hepatic Nicotine Metabolism and a CYP2A6-Like Enzyme in African Green Monkeys after Long-Term Nicotine Administration

Kerri A. Schoedel, Edward M. Sellers, Roberta Palmour and Rachel F. Tyndale
Molecular Pharmacology January 1, 2003, 63 (1) 96-104; DOI: https://doi.org/10.1124/mol.63.1.96
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