Clinical Information

Arylamine N-acetyltransferase type 2 (NAT2) is a highly polymorphic phase 2 metabolic enzyme that conjugates hydrazine derivatives and aromatic amine drugs with acetyl-groups.(1) NAT2 also is involved in the acetylation and activation of some procarcinogens.(1,2)

Individuals acetylate drugs at different rates by NAT2 and are described as having slow, intermediate, or rapid (fast) acetylator phenotypes. Some studies, which have examined diversity of NAT2 haplotypes among individuals of different ethnicities hypothesize that the NAT2 slow acetylator phenotype was positively selected for in the transition from hunter-gatherer or nomadic lifestyle to an agricultural or pastoral lifestyle.(3) The prevalence of slow acetylator phenotypes increases with decreasing distance to the equator. Near the equator, up to 80% of individuals may be slow acetylators, while in some more northern countries, as few as 10% of the population may have the slow acetylator phenotype.

A number of drugs are metabolized by NAT2 including procainamide, dapsone, nitrazepam, hydralazine, sulfasalazine, amifampridine, and isoniazid.(4) Isoniazid is used to treat and prevent tuberculosis and is still used as a primary treatment agent. Adverse reactions with isoniazid, which include nausea, drug-induced hepatitis, peripheral neuropathy, and sideroblastic anemia, are associated more often with a slow NAT2 acetylator phenotype. These individuals may require a lower dose to avoid adverse reactions.(4) Of note, acetaminophen is a significant NAT2 inhibitor.

The NAT2 gene contains a single intronless exon of 870 base pairs and encodes 290 amino acids. NAT2 is highly polymorphic and contains at least 16 known single nucleotide variants and 1 single base pair deletion. These genetic variants are combined into 36 known haplotypes or alleles. Each individual haplotype is predictive of either a rapid (fast) or slow acetylator phenotype. Individuals with 2 rapid haplotypes are predicted to be rapid (normal) metabolizers, while those with 1 rapid and 1 slow haplotype are intermediate metabolizers, and those with 2 slow haplotypes are poor metabolizers.(5,6) Studies with patients who have different acetylator haplotypes have correlated the ratio of plasma N-acetylisoniazid/isoniazid drug concentrations with haplotypes, with slow and intermediate acetylators having lower ratios than rapid acetylators.(7)

NAT2 genotype results are used to predict metabolizer phenotypes, as indicated in the Table. Note that the reference allele for NAT2 is *4. If no variants are detected, the default genotype and phenotype reported are *4/*4 and rapid acetylator phenotype, respectively.

Table.