Genetic Polymorphism inN-Acetyltransferase (NAT): Population Distribution of NAT1 and NAT2 Activity

Abstract

N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity produced by the anti-tubercular drug isoniazid, with molecular epidemiologic studies suggesting a link between acetylator phenotype and increased risk for bladder cancer. Recent evidence indicates that the other major NAT isozyme, NAT1, is also polymorphic. The current analysis characterizes the main polymorphisms in both NAT2 and NAT1 in terms of their effect on enzyme activity and frequency in the population. Multiple NAT2 alleles (NAT2*5, *6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasians and populations of African descent. In these groups, most individuals carry at least one copy of a slow acetylator allele, and less than 10% are homozygous for the wild type (fast acetylator) trait. Incorporation of these data into a Monte Carlo modeling framework led to a population distribution of NAT2 activity that was bimodal and associated with considerable variability in each population assessed. The ratio of the median to the first percentile of NAT2 activity ranged from 7 in Caucasians to 18 in the Chinese population. This variability indicates the need for more quantitative approaches (e.g., physiologically based pharmacokinetic [PBPK] modeling) to assess the full distribution of internal dose and adverse responses to aromatic amines and other NAT2 substrates. Polymorphisms in NAT1 are generally associated with relatively minor effects on acetylation function, with Monte Carlo analysis indicating less interindividual variability than seen in NAT2 analysis.

Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples

“…NAT 2 is also a polymorphic enzyme, and around half of a Caucasian population have a marked reduction in NAT 2 activity (20). In our study, ratios between the acetamido metabolite and the amino metabolite (in the hydrolyzed samples) were 0.47, 0.39, and 0.24 in cases H2, H3, and H4 while in case H1, the ratio was 1.21 which could possibly be caused by a higher NAT 2 activity in this case.…”

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population

“…The major alleles groups associated with decreased enzyme activity due to amino acid changes and, therefore, a slow acetylator phenotype, are NAT-2*5, NAT-2*6, NAT-2*7 and NAT-2*14 [4]; in several surveys homozygous wild type alleles at all four loci that have no variations are called RA and are represented as NAT-2*4 [4][5][6][7].…”

Association between N-acetyltransferase 2 polymorphisms and pancreatic cancer risk: a meta-analysis

“…NAT2 catalyzes the detoxification or activation of aromatic and heterocyclic amine carcinogens by N-acetylation detoxification or by O-acetylation activation (Liu et al, 2009). NAT2 genetic variation might lead to an increased risk of different type of cancer (Walker et al, 2009). However, the questions of whether NAT2 polymorphism is significantly associated with the risk of pancreatic cancer and the identity of the mechanism underlying the potential association are still in need of further exploration.…”