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Titolo:
Duplications and defects in the CYP2A6 gene: Identification, genotyping, and in vivo effects on smoking
Autore:
Rao, YS; Hoffmann, E; Zia, M; Bodin, L; Zeman, M; Sellers, EM; Tyndale, RF;
Indirizzi:
Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 macol, Toronto, ON M5S 1A8, Canada Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 chiat, Toronto, ON M5S 1A8, Canada Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 t Med, Toronto, ON M5S 1A8, Canada Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 Hlth, Toronto, ON M5S 1A8, Canada Univ Toronto, Ctr Res Womens Hlth, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 Hlth, Toronto, ON M5S 1A8, Canada
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 4, volume: 58, anno: 2000,
pagine: 747 - 755
SICI:
0026-895X(200010)58:4<747:DADITC>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; CYTOCHROME-P450 2A6 CYP2A6; COUMARIN 7-HYDROXYLATION; NICOTINE METABOLISM; LUNG-CANCER; DELETION; POLYMORPHISM; POPULATION; FREQUENCY; SEQUENCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: Tyndale, RF Univ Toronto, Dept Pharmacol, 1 Kings Coll Circle, Toronto, ONM5S 1A8, Canada Univ Toronto 1 Kings Coll Circle Toronto ON Canada M5S 1A8ada
Citazione:
Y.S. Rao et al., "Duplications and defects in the CYP2A6 gene: Identification, genotyping, and in vivo effects on smoking", MOLEC PHARM, 58(4), 2000, pp. 747-755

Abstract

In humans, 80% of nicotine is metabolized to the inactive metabolite cotinine by the enzyme CYP2A6, which can also activate tobacco smoke procarcinogens (e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). Previously, we demonstrated that individuals who are nicotine-dependent and have defectiveCYP2A6 alleles (* 2, *3) smoked fewer cigarettes; however, we recognize that the genotyping method used for the CYP2A6*3 allele gave a high false-positive rate. In the current study we used improved genotyping methods to examine the effects of the defective CYP2A6*2 and CYP2A6*4 alleles on smoking behavior. We found that those with the defective alleles (N = 14) smoked fewer cigarettes per day than those homozygous (N = 277) for wild-type alleles (19 versus 28 cigarettes per day, P < .001). In addition, we identified aduplicated form of the CYP2A6 gene, corresponding to the gene deletion CYP2A6*4 allele, developed a genotyping assay, assessed the gene copy number, and examined its prevalence in Caucasian smokers (N = 296). We observed an ascending rank order for plasma cotinine and breath carbon monoxide levels (an index of smoke inhalation) in individuals with null (CYP2A6*2 and CYP2A6*4) alleles (N = 14), those homozygous for wild-type (CYP2A6*1/*1) alleles(N = 277), and those with our newly identified CYP2A6 gene duplication (N = 5). The phenotype, as determined by plasma nicotine/cotinine ratios, had a descending rank order for these three genotype groups that did not reach significance. Although further characterization is required for the duplication gene variant, these results extend our previous findings and suggest asubstantial influence of CYP2A6 genotype and phenotype on smoking behavior.

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Documento generato il 15/07/20 alle ore 14:45:56