title: Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism.
abstract: Cytochrome P450 2A6 (CYP2A6) is the human enzyme responsible for the majority of nicotine's metabolism. CYP2A6 genetic variants contribute to the interindividual and interethnic variation in nicotine metabolism. We examined the association between the CYP2A6*1B variant and nicotine's in vivo metabolism. Intravenous infusions of deuterium-labeled nicotine were administered to 292 volunteers, 163 of whom were White and did not have common CYP2A6 variants, other than CYP2A6*1B. We discovered three novel CYP2A6*1B variants in the 3'-flanking region of the gene that can confound genotyping assays. We found significant differences between CYP2A6*1A/*1A, CYP2A6*1A/*1B, and CYP2A6*1B/*1B groups in total nicotine clearance (17.2+/-5.2, 19.0+/-6.4, and 20.4+/-5.9, P<0.02), non-renal nicotine clearance (16.4+/-5.0, 18.5+/-6.2, and 19.8+/-5.7, P<0.01), and the plasma trans-3'-hydroxycotinine/cotinine ratio (0.26+/-0.1, 0.26+/-0.1, and 0.34+/-0.1, P<0.001). There were also differences in total nicotine (29.4+/-12.9, 25.8+/-0.12.9, and 22.4+/-12.4, P<0.01), cotinine (29.2+/-8.1, 32.2+/-9.1, and 33.0+/-6.6, P<0.01) and trans-3'-hydroxycotinine (32.4+/-9.1, 34.2+/-12.3, and 41.3+/-11.3, P<0.001) excreted in the urine. We report evidence that CYP2A6*1B genotype is associated with faster nicotine clearance in vivo, which will be important to future CYP2A6 genotype association studies.
authors.affiliation: Department of Pharmacology, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: Mwenifumbo
authors.forename: C N
authors.initials: CN
authors.lastname: Lessov-Schlaggar
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.forename: R E
authors.initials: RE
authors.lastname: Krasnow
authors.forename: G E
authors.initials: GE
authors.lastname: Swan
authors.forename: N L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: R F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D024509:3' Flanking Region; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001711:Biotransformation; D003367:Cotinine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D065637:Cytochrome P-450 CYP2A6; D003903:Deuterium; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D005965:Glucuronates / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009538:Nicotine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010641:Phenotype; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: D005965:Glucuronates; D018722:Nicotinic Agonists; C075991:cotinine N-glucuronide; C085795:nicotine N-glucuronide; C001381:hydroxycotinine; D009538:Nicotine; D003903:Deuterium; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine