Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration.
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 < or = 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.
Schoedel
Kerri A
KA
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Sellers
Edward M
EM
Palmour
Roberta
R
Tyndale
Rachel F
RF
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D065637:Cytochrome P-450 CYP2A6; D015536:Down-Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D009538:Nicotine / Q000493:pharmacokinetics / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects
D018722:Nicotinic Agonists; D012333:RNA, Messenger; D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6