The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans.
Pharmacogenet Genomics
; 21(7): 403-16, 2011 Jul.
Article
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| MEDLINE
| ID: mdl-21597399
ABSTRACT
OBJECTIVE:
To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism.METHODS:
The conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes.RESULTS:
The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5'-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02).CONCLUSION:
Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Hidrocarburo de Aril Hidroxilasas
/
Nicotina
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Pharmacogenet Genomics
Asunto de la revista:
FARMACOLOGIA
/
GENETICA MEDICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos