N-acetyltransferase 2 genotyping: an accurate and feasible approach for simultaneous detection of the most common NAT2 alleles.

Abstract

N -Acetyltransferase 2 (NAT2; EC 2.3.1.5) is involved in the detoxification of numerous xenobiotics. The human NAT2 gene is highly polymorphic and represents one of the best studied examples of the large interindividual variability of genetic control of drug or xenobiotic metabolism. In addition to the antituberculosis agent isoniazid (1), the first NAT2 substrate discovered, numerous other chemicals possessing a primary aromatic amine or hydrazine group, such as sulfamethazine, procainamide, hydralazine (2), dapsone, nitrazepam, and caffeine, are metabolized by this enzyme. Arylamine chemicals such as benzidine, β-naphthylamine, and 2-aminofluorene can also be acetylated by NAT2. As early as 1970, Reidenberg et al.(3) reported clinical problems associated with polymorphic acetylation of procainamide. The determination of NAT2 genotype or NAT2 phenotype has been proposed as a way to predict adverse reactions in patients with tuberculosis and before the concomitant administration of procainamide and phenytoin (4). The proportions of rapid and slow phenotypes vary in different ethnic groups. In Caucasians, 40–70% of individuals have the slow acetylator phenotype, whereas Asian populations have only 10–30% slow acetylators (5). Several single-nucleotide polymorphisms have been identified in the human NAT2 coding region, which are responsible for the observed phenotypes [see Ref. (6); accession no. X14672]. The presence of the NAT2 * 4 (wild-type) allele defines the NAT2 genotype as rapid, and combinations of the frequently occurring mutant alleles NAT2 * 5B , * 5C , * 6A , * 7B , and * 14 cluster as slow. Allele frequencies in Caucasians are 23% for NAT2 * 4 (wild type), 1.3% for * 5A , 35% for * 5B , 5.0% for * 5C , 30.5% for * 6A , 4.5% for * 7B , and 0.2% for …