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HERO ID
194764
Reference Type
Journal Article
Subtype
Review
Title
Genetic polymorphism in N-acetyltransferase (NAT): population distribution of NAT1 and NAT2 activity
Author(s)
Walker, K; Ginsberg, G; Hattis, D; Johns, D; Guyton, KZ; Sonawane, B
Year
2009
Is Peer Reviewed?
1
Journal
Journal of Toxicology and Environmental Health
ISSN:
0098-4108
Volume
12
Issue
5-6
Page Numbers
440-472
Language
English
PMID
20183529
DOI
10.1080/10937400903158383
Web of Science Id
WOS:000271375100005
URL
https://www.proquest.com/scholarly-journals/genetic-polymorphism-n-acetyltransferase-nat/docview/1777132875/se-2?accountid=171501
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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.
Keywords
Mechanical & Transportation Engineering Abstracts (MT); Environmental Engineering Abstracts (EN); CSA / ASCE Civil Engineering Abstracts (CE); Acetylation; Computer simulation; Monte Carlo methods; Polymorphism; Enzymes; Reproduction; Population distribution
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