PT  - JOURNAL ARTICLE
AU  - Kerri A. Schoedel
AU  - Edward M. Sellers
AU  - Roberta Palmour
AU  - Rachel F. Tyndale
TI  - Down-Regulation of Hepatic Nicotine Metabolism and a CYP2A6-Like Enzyme in African Green Monkeys after Long-Term Nicotine Administration
AID  - 10.1124/mol.63.1.96
DP  - 2003 Jan 01
TA  - Molecular Pharmacology
PG  - 96--104
VI  - 63
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/63/1/96.short
4100  - http://molpharm.aspetjournals.org/content/63/1/96.full
SO  - Mol Pharmacol2003 Jan 01; 63
AB  - 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.