School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072 Australia.
Pharmacol Rev. 2012 Jan;64(1):147-65. doi: 10.1124/pr.110.004275. Epub 2011 Nov 16.
The human arylamine N-acetyltransferases first attracted attention because of their role in drug metabolism. However, much of the current literature has focused on their role in the activation and detoxification of environmental carcinogens and how genetic polymorphisms in the genes create predispositions to increased or decreased cancer risk. There are two closely related genes on chromosome 8 that encode the two human arylamine N-acetyltransferases--NAT1 and NAT2. Although NAT2 has restricted tissue expression, NAT1 is found in almost all tissues of the body. There are several single-nucleotide polymorphisms in the protein coding and 3'-untranslated regions of the gene that affect enzyme activity. However, NAT1 is also regulated by post-translational and environmental factors, which may be of greater importance than genotype in determining tissue NAT1 activities. Recent studies have suggested a novel role for this enzyme in cancer cell growth. NAT1 is up-regulated in several cancer types, and overexpression can lead to increased survival and resistance to chemotherapy. Although a link to folate homeostasis has been suggested, many of the effects attributed to NAT1 and cancer cell growth remain to be explained. Nevertheless, the enzyme has emerged as a viable candidate for drug development, which should lead to small molecule inhibitors for preclinical and clinical evaluation.
人类芳香胺 N-乙酰基转移酶最初因其在药物代谢中的作用而引起关注。然而，目前的大部分文献都集中在其在环境致癌剂的激活和解毒中的作用，以及基因中的遗传多态性如何导致癌症风险增加或降低的易感性。8 号染色体上有两个密切相关的基因，编码两种人类芳香胺 N-乙酰基转移酶——NAT1 和 NAT2。虽然 NAT2 的组织表达受限，但 NAT1 几乎存在于体内所有组织中。该基因的蛋白质编码区和 3'-非翻译区有几个单核苷酸多态性，影响酶活性。然而，NAT1 也受到翻译后和环境因素的调节，这些因素在决定组织 NAT1 活性方面可能比基因型更为重要。最近的研究表明，该酶在癌细胞生长中具有新的作用。NAT1 在几种癌症类型中上调，过表达可导致存活增加和化疗耐药性。虽然已经提出了与叶酸稳态的联系，但许多归因于 NAT1 和癌细胞生长的影响仍有待解释。尽管如此，该酶已成为药物开发的可行候选物，这将导致用于临床前和临床评估的小分子抑制剂。
