Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.
Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.
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DOI：
10.1097/fpc.0b013e3283498ee9
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发表时间：
2011-10
影响因子：
2.6
通讯作者：
Sadee W
中科院分区：
文献类型：
--
作者：
Wang D;Para MF;Koletar SL;Sadee W
N-乙酰基转移酶1（NAT 1）代谢药物和环境致癌物。与野生型NAT 1 *4相比，NAT 1等位基因 *10和 *11已被提出改变蛋白质水平或酶活性，并通过不确定的途径赋予癌症风险。本研究的特点是调节多态性和NAT 1表达的潜在机制。我们测量了等位基因NAT 1 mRNA的表达和翻译，作为多个转录起始位点、选择性剪接和3个3′-聚腺苷酸化位点在人肝脏（本研究中发现了其中一个）、B淋巴细胞和转染细胞中的功能。在一项对469名接受NAT 1/NAT 2底物磺胺甲恶唑（SMX）治疗的HIV/AIDS患者的临床研究中，检测了SMX诱导的超敏反应与NAT 1 *10和 *11基因型以及已知的NAT 2多态性之间的关联。NAT 1 *10和 *11被确定为占大多数NAT 1表达变异性的共同调节等位基因，两者都导致增加的翻译成活性蛋白。NAT 1 *11（2.4%次要等位基因频率）影响3′多聚腺苷酸化位点的使用，从而增加了具有中等长度3′UTR（主要异构体）的NAT 1 mRNA的形成，而牺牲了短异构体，导致更有效的蛋白质翻译。NAT 1 *10（19%次要等位基因频率）增加翻译效率而不影响3′-UTR多聚腺苷酸化位点的使用。*11/*4和 *10/*10基因型的肝脏和B淋巴细胞显示出比参考基因型 *4/*4更高的NAT 1免疫反应性和NAT 1酶活性。携带 *10/*10和 *11/*4（“快速NAT 1乙酰化”）的患者不太可能对SMX产生超敏反应，但这仅在携带慢速NAT 2乙酰化基因型的受试者中观察到。NAT 1 *10和 *11显著增加NAT 1蛋白水平/酶活性，使携带者能够分类为参考和快速乙酰化。快速NAT 1乙酰化状态似乎通过补偿缓慢NAT 2乙酰化状态来保护SMX毒性。
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 to wild-type NAT1 *4 and to confer cancer risk, via 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 discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 HIV/AIDS patients 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′UTR (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′-UTR 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 subjects 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 appears to protect against SMX toxicity by compensating for slow NAT2 acetylator status.