Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption.
The rates of nicotine metabolism differ widely, even after controlling for genetic variation in the major nicotine-metabolizing enzyme, CYP2A6. Genetic variants in an additional nicotine-metabolizing enzyme, flavin-containing monooxygenase (FMO)-3, and an obligate microsomal CYP-supportive enzyme, cytochrome P450 oxidoreductase (POR), were investigated. We examined the impact of FMO3 E158K and POR A503V before and after stratifying by CYP2A6 metabolism group. In 130 nonsmokers of African descent who received 4 mg oral nicotine, FMO3 158K trended toward slower nicotine metabolism in reduced CYP2A6 metabolizers (P=0.07) only, whereas POR 503V was associated with faster CYP2A6 activity (nicotine metabolite ratio) in normal (P=0.03), but not reduced, CYP2A6 metabolizers. Neither FMO3 158K nor POR 503V significantly altered the nicotine metabolic ratio (N=659), cigarette consumption (N=667), or urine total nicotine equivalents (N=418) in smokers of African descent. Thus, FMO3 E158K and POR A503V are minor sources of nicotine metabolism variation, insufficient to appreciably alter smoking.
aDepartments of Psychiatry and Pharmacology and Toxicology, Centre for Addiction and Mental Health (CAMH), Campbell Family Mental Health Research Institute, University of Toronto, Toronto, Ontario, Canada bDepartment of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas cDepartment of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota dDivision of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California, USA.
Meghan J
MJ
Chenoweth
Andy Z X
AZ
Zhu
Lisa
L
Sanderson Cox
Jasjit S
JS
Ahluwalia
Neal L
NL
Benowitz
Rachel F
RF
Tyndale
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044383:Black People / Q000235:genetics; D065637:Cytochrome P-450 CYP2A6; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008657:Metabolic Clearance Rate; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D009538:Nicotine / Q000493:pharmacokinetics* / Q000652:urine*; D010105:Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*
D009538:Nicotine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D009251:NADPH-Ferrihemoprotein Reductase