Abstract
BackgroundN-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. In fact, the evolutionary and ethnic-specific SNPs on the NAT2 gene remain a focus for the potential discoveries in personalized drug therapy and genetic markers of diseases. Despite the wide characterization of NAT2 SNPs frequency in established ethnic groups, little data are available for highly admixed populations. In this context, five common NAT2 SNPs (G191A, C481T, G590A, A803G and G857A) were investigated in a highly admixed population comprised of Afro-Brazilians, Whites, and Amerindians in northeastern Brazil. Thus, we sought to determine whether the distribution of NAT2 polymorphism is different among these three ethnic groups.ResultsOverall, there were no statistically significant differences in the distribution of NAT2 polymorphism when Afro-Brazilian and White groups were compared. Even the allele frequency of 191A, relatively common in African descendents, was not different between the Afro-Brazilian and White groups. However, allele and genotype frequencies of G590A were significantly higher in the Amerindian group than either in the Afro-Brazilian or White groups. Interestingly, a haplotype block between G590A and A803G was verified exclusively among Amerindians.ConclusionsOur results indicate that ethnic admixture might contribute to a particular pattern of genetic diversity in the NAT2 gene and also offer new insights for the investigation of possible new NAT2 gene-environment effects in admixed populations.
Highlights
N-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines
Special emphasis has been placed on a phase II metabolizing enzyme, N-acetyltransferase type 2 (Nat2, EC 2.3.1.5), a milestone in the pharmacogenetics field as one of the first enzymes to be associated as a cause of interindividual variation in drug metabolism [3]
The allele and genotype frequencies of the NAT2 single nucleotide polymorphisms (SNPs) obtained from all individuals and in separate ethnic groups are summarized in Table 2. 481T was the most frequent allele with 38.79% in the general
Summary
N-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Despite the wide characterization of NAT2 SNPs frequency in established ethnic groups, little data are available for highly admixed populations. Genetic functional polymorphisms of xenobiotic/drug metabolizing enzymes have been associated with pharmacotherapy response differences and disease risk susceptibility [1,2]. Nat catalyzes a transfer of an acetyl group from the cofactor acetyl-coenzyme A (acetyl-CoA) to the amine nitrogen atom of aromatic amines and hydrazines [4] This enzyme is important in the aromatic and. The effects of genetic polymorphism in the NAT2 gene on N-acetylation activity led to investigations of NAT2 SNPs as a promising genetic marker for disease risk, drug response therapy and/or adverse reactions to drugs [13]. Some authors demonstrated increased risk of myelotoxicity induced by amonafide in rapid acetylators, probably due to the production of higher levels of toxic metabolites from drugs [15]
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