Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis
Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis
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DOI：
10.1016/s0027-5107(02)00153-7
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发表时间：
2002-09-30
影响因子：
2.3
通讯作者：
Hein, DW
中科院分区：
文献类型：
--
作者：
Hein, DW
芳香胺和杂环胺需要代谢活化为引发致癌作用的亲电中间体。N-乙酰转移酶1（NAT 1）和2（NAT 2）是这些致癌物生物转化的重要酶，并表现出遗传多态性。人类NAT 1和NA 72等位基因由国际基因命名委员会在www.example.com.html上列出。http://www.louisville.edu/medschool/pharmacology/NAT在人群中的高频率的NAT 1和NAT 2乙酰化多态性，以及无处不在的暴露于芳香族和杂环胺表明，NAT 1和NAT 2乙酰化基因型是人类癌症易感性的重要修饰剂。对于N-乙酰化是解毒步骤的癌症，如芳香胺相关的膀胱癌，NAT 2慢乙酰化表型的风险更高。多项研究表明，膀胱癌的风险在最慢的NAT 2乙酰化表型或基因型（NAT 2 *5）中特别高。相比之下，对于N-乙酰化可以忽略不计并且O-乙酰化是活化步骤的癌症，例如对于杂环胺相关的结肠癌，NAT 2快速乙酰化表型处于较高风险。尽管研究发现NAT 1基因型与各种癌症之间存在关联，但这些发现不太一致，也不太清楚。由于癌症风险需要暴露于由NAT 1和/或NAT 2乙酰化基因型修饰的芳香族和/或杂环胺致癌物，因此人类流行病学研究的结果取决于暴露评估和基因型测定的质量和准确性。结论需要了解基因型和表型之间的关系，以及遗传变异在致癌物质代谢，DNA修复和宿主易感性中的作用。已在暴露和遗传变异均受到严格控制的快速和缓慢乙酰化啮齿动物模型中进行了研究。人类NAT 1和NAT 2等位基因已通过重组表达来表征，以进一步了解核苷酸多态性对功能和表型的影响。(C)2002 Elsevier Science BX保留所有权利。
Aromatic and heterocyclic amines require metabolic activation to electrophilic intermediates that initiate carcinogenesis. N-Acetyltransferase 1 (NAT 1) and 2 (NAT2) are important enzymes in the biotransformation of these carcinogens and exhibit genetic polymorphism. HumanNAT1 and NA72 alleles are listed at: http://www.louisville.edu/medschool/pharmacology/NAT. html by an international gene nomenclature committee. The high frequency of the NAT1 and NAT2 acetylation polymorphisms in human populations together with ubiquitous exposure to aromatic and heterocyclic amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. For cancers in which N-acetylation is a detoxification step such as aromatic amine-related urinary bladder cancer, NAT2 slow acetylator phenotype is at higher risk. Multiple studies have shown that the urinary bladder cancer risk is particularly high in the slowest NAT2 acetylator phenotype or genotype (NAT2*5). In contrast, for cancers in which N-acetylation is negligible and O-acetylation is an activation step such as for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype is at higher risk. Although studies have found associations between NAT1 genotype and various cancers, the findings are less consistent and are not well understood. Since cancer risk requires exposure to aromatic and/or heterocyclic amine carcinogens modified by NAT1 and/or NAT2 acetylator genotype, the results from human epidemiology studies are dependent upon the quality and accuracy of the exposure assessment and genotype determination. Conclusions require understanding the relationship between genotype and phenotype, as well as the role of genetic variation in carcinogen metabolism, DNA repair, and host susceptibility. Investigations have been carried out in rapid and slow acetylator rodent models in which both exposure and genetic variability are tightly controlled. Human NAT1 and NAT2 alleles have been characterized by recombinant expression to further understand the effects of nucleotide polymorphisms on function and phenotype. (C) 2002 Elsevier Science BX All rights reserved.