Lack of association between human longevity and genetic polymorphisms in drug-metabolizing enzymes at the NAT2, GSTM1 and CYP2D6 loci.

Abstract

In the present study, the possible role of genetic polymorphism of three drug-metabolizing enzymes, debrisoquine/sparteine hydroxylase (CYP2D6), glutathione S-transferase mu (GSTM1), and N-acetyltransferase (NAT2), as a putative genetic component of human longevity, was explored. A total of 817 DNA samples from a centenarian and a control (20-70 years) population was subjected to PCR-coupled RFLP methods. Subjects were genotyped for the CYP2D6*3 (A2637 deletion) and CYP2D6*4 (G1934A transition) alleles, for four mutations of NAT2 [namely, NAT2*5A (C481T), NAT2*6A (G590A), NAT2*7A (G857A), and NAT2*14A (G191A)], and for the presence or absence of GSTM1 gene deletion. No significant difference was found at these three loci between centenarian and control subjects with respect to allelic variant frequencies, genotype distributions or predicted phenotypes deduced from genotype combinations. By comparing the distribution of combined genotypes for the polymorphisms tested at the CYP2D6, NAT2, and GSTM1 loci, none of the predicted phenotypes concerning debrisoquine hydroxylase extensive-metabolizer or poor-metabolizer phenotypes, slow or fast N-acetylation capacities, and active or defective glutathione S-transferase, could be correlated with human longevity, alone or in combination.