title: Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations.
abstract: Human cytochrome P450 (CYP) 2A6 metabolizes nicotine to cotinine and is a possible modulator of nicotine addiction. Quantitative and qualitative differences in nicotine addiction have been observed between ethnic groups. However, there are few data on the ethnic influences of the CYP2A6-nicotine metabolism relationship, particularly with regard to black subjects. We determined the nicotine metabolism and CYP2A6 genotype in 176 white subjects and 160 black subjects, comparing them with our previous data from 209 Korean subjects and 92 Japanese subjects. Large interindividual differences were observed in the cotinine/nicotine ratios in plasma calculated as an index of nicotine metabolism in white subjects (range, 0.6-36.5) and in black subjects (range, 0.9-30.4). No ethnic difference in the metabolic ratio was observed among white subjects (mean, 7.2 +/- 5.0), black subjects (mean, 7.1 +/- 4.7), and Korean subjects (mean, 8.7 +/- 11.9), whereas Japanese subjects showed a significantly (P < .005) lower metabolic ratio (mean, 3.8 +/- 3.1) compared with the other populations. Women showed significantly (P < .05) higher metabolic ratios than men in the black population (8.0 +/- 5.3 versus 6.0 +/- 3.7). Obvious ethnic differences in the CYP2A6 alleles were observed among these 4 populations. The combined frequencies of the alleles lacking or showing reduced enzymatic activity (CYP2A6*2, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*9, CYP2A6*10, CYP2A6*11, CYP2A6*17, CYP2A6*19, and CYP2A6*20) were 9.1%, 21.9%, 42.9%, and 50.5% in white, black, Korean, and Japanese subjects, respectively. These CYP2A6 alleles were associated with reduced nicotine metabolism. Among the homozygotes of CYP2A6*1, interindividual and ethnic differences in the metabolic ratio were still observed. Thus some factors other than genetic ones might also contribute to the interindividual and ethnic differences. This comprehensive study of 4 populations extends our understanding of nicotine metabolism and the impact of genetic polymorphisms of the CYP2A6 gene.
authors.affiliation: Department of Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa, Japan. nmiki@kenroku.kanazawa-u.ac.jp <nmiki@kenroku.kanazawa-u.ac.jp>
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Eriko
authors.initials: E
authors.lastname: Higashi
authors.forename: Haruko
authors.initials: H
authors.lastname: Sakai
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yoshida
authors.forename: Jun-Tack
authors.initials: JT
authors.lastname: Kwon
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics*; D002638:Chewing Gum; D003367:Cotinine / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D005731:Ganglionic Stimulants / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D007723:Korea; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012737:Sex Factors; D013997:Time Factors; D044465:White People / Q000235:genetics*
chemical_list: D002638:Chewing Gum; D005731:Ganglionic Stimulants; D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine