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- Title
Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.
- Authors
Al Koudsi, Nael; Mwenifumbo, Jill C.; Sellers, Edward M.; Benowitz, Neal L.; Swan, Gary E.; Tyndale, Rachel F.
- Abstract
Objective: The impact of CYP2A6*21 (K476R) on in vivo nicotine metabolism and disposition was investigated. Methods: A two-step allele-specific PCR assay was developed to detect the 6573A>G single nucleotide polymorphism (SNP) in CYP2A6*21. Nicotine metabolism phenotypes from a previously described intravenous labeled nicotine and cotinine infusion study [1] was used to assess the impact of CYP2A6*21. Genomic DNA samples from 222 (111 monozygotic and dizygotic twin pairs) Caucasian subjects were genotyped for CYP2A6 alleles (CYP2A6*1X2, -*1B, -*2, -*4, -*7, -*9, -*10, -*12, and -*21). The pharmacokinetic parameters were compared between individuals with no detected CYP2A6 variants (CYP2A6*1/*1, n=163) and individuals heterozygous for the CYP2A6*21 allele (CYP2A6*1/*21, n=9). Results: The frequency of the CYP2A6*21 allele was found to be 2.3% in Caucasians (n=5/222 alleles, evaluated in one twin from each twin pair). In vivo pharmacokinetic parameters, such as nicotine clearance (1.32±0.37 vs. 1.18±0.20 L/min), fractional clearance of nicotine to cotinine (1.02±0.36 vs. 0.99± 0.23 L/min), nicotine half-life (111±37 vs. 116± 29min), and the trans-3′-hydroxycotinine to cotinine ratio (1.92±1.0 vs. 1.55±0.58) indicated no substantial differences in nicotine metabolism between those without the variant (CYP2A6*1/*1, n=163) and those with the variant (CYP2A6*1/*21, n=9), respectively. Conclusions: CYP2A6*21 does not have a detectable impact on nicotine metabolism in vivo. Our data suggest that CYP2A6*21 may not be important for future studies of nicotine metabolism and the resulting impacts on smoking behaviors.
- Subjects
NICOTINE; TOBACCO; METABOLISM; BIOCHEMISTRY; GENETICS; PHENOTYPES; DNA; GENES; SMOKING
- Publication
European Journal of Clinical Pharmacology, 2006, Vol 62, Issue 6, p481
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-006-0113-3