Clark University, Center for Technology, Environment, and Development, Worcester, Massachusetts, USA.
J Toxicol Environ Health B Crit Rev. 2009;12(5-6):440-72. doi: 10.1080/10937400903158383.
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.
N-乙酰基转移酶（NAT）是将某些药物和其他芳香胺结构的外源化学物质与芳胺结构结合的关键酶。长期以来，NAT2 的多态性被认为可以调节抗结核药物异烟肼的毒性，分子流行病学研究表明乙酰化表型与膀胱癌风险增加之间存在关联。最近的证据表明，另一种主要的 NAT 同工酶 NAT1 也是多态的。目前的分析从酶活性和人群频率的角度描述了 NAT2 和 NAT1 中的主要多态性。多种 NAT2 等位基因（NAT2*5、*6、7 和14）的乙酰化活性显著降低，在白种人和非洲裔人群中很常见。在这些群体中，大多数个体至少携带一个慢乙酰化等位基因的副本，不到 10%的个体是野生型（快乙酰化）纯合子。将这些数据纳入蒙特卡罗建模框架，导致 NAT2 活性的人群分布呈双峰分布，并与每个评估人群中的显著变异性相关。NAT2 活性的中位数与第一百分位数的比值范围从白种人中的 7 到中国人中的 18。这种变异性表明需要更定量的方法（例如，基于生理学的药代动力学[PBPK]建模）来评估芳香胺和其他 NAT2 底物的内部剂量和不良反应的全部分布。NAT1 的多态性通常与乙酰化功能的相对较小影响相关，蒙特卡罗分析表明个体间变异性小于 NAT2 分析。
