Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, Ohio State University, Columbus, Ohio 43210, USA.
Pharmacogenet Genomics. 2011 Oct;21(10):652-64. doi: 10.1097/FPC.0b013e3283498ee9.
N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.
We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3'-polyadenylation sites in human livers (one of which was discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 patients with HIV/AIDS treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX-induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.
NAT1 *10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1 *11 (2.4% minor allele frequency) affected 3'-polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3'-untranslated region (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3'-untranslated region polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (fast NAT1 acetylators) were less likely to develop hypersensitivity to SMX, but this was observed only in individuals who are also carrying a slow NAT2 acetylator genotype.
NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status seems to protect against SMX toxicity by compensating for slow NAT2 acetylator status.
N-乙酰基转移酶 1（NAT1）代谢药物和环境致癌物。与野生型 NAT14 相比，NAT1 等位基因10 和*11 被提议改变蛋白水平或酶活性，并通过不确定的途径赋予癌症风险。本研究描述了 NAT1 表达的调节多态性和潜在机制。
我们测量了人肝、B 淋巴细胞和转染细胞中多个转录起始位点、选择性剪接以及三个 3'多聚腺苷酸化位点（其中一个在本研究中发现）的等位基因 NAT1 mRNA 表达和翻译。在一项对 469 名接受 NAT1/NAT2 底物磺胺甲恶唑（SMX）治疗的 HIV/AIDS 患者的临床研究中，测试了 NAT110 和11 基因型与 SMX 诱导的过敏反应之间的关联，以及已知的 NAT2 多态性。
确定 NAT110 和11 作为常见的调节等位基因，占 NAT1 表达变异性的大部分，均导致活性蛋白翻译增加。NAT111（2.4%的次要等位基因频率）影响 3'多聚腺苷酸化位点的使用，从而增加了具有中间长度 3'非翻译区（主要同工型）的 NAT1 mRNA 的形成，而牺牲了短同工型，从而导致更有效的蛋白质翻译。NAT110（19%的次要等位基因频率）增加了翻译效率，而不影响 3'非翻译区多聚腺苷酸化位点的使用。携带*11/4 和10/10 基因型的肝和 B 淋巴细胞显示出比参考基因型4/4 更高的 NAT1 免疫反应性和 NAT1 酶活性。携带10/10 和11/*4（快速 NAT1 乙酰化酶）的患者不太可能对 SMX 产生过敏反应，但这仅在携带缓慢 NAT2 乙酰化酶基因型的个体中观察到。
NAT110 和11 显著增加了 NAT1 蛋白水平/酶活性，能够将携带者分类为参考和快速乙酰化酶。快速 NAT1 乙酰化酶状态似乎通过补偿缓慢的 NAT2 乙酰化酶状态来保护免受 SMX 毒性。
