Acetaminophen Pharmacogenetics

描述（由申请人提供）：对乙酰氨基酚（APAP）是美国最常用的药物，但也是药物性肝毒性的最常见原因。本研究的长期目标是阐明导致APAP诱导肝毒性个体风险差异的药物遗传学机制。我们的工作假设是，基因多态性，修改的酶和调节蛋白的表达和功能，参与APAP的净化和解毒，可用于识别个人有增加的风险APAP肝毒性。这项工作的主要重点是编码酶的基因，这些酶已被确定为这些途径的关键，包括UDP-葡萄糖醛酸转移酶（UGT），磺基转移酶（SULT）和细胞色素P450（CYP）。在初步工作中，我们确定了UGT 1A 1、1A 6和1A 9为主要的APAP葡萄糖醛酸化酶，并在UGT 1A 6基因中确定了3个连锁的氨基酸多态性，这些多态性改变了重组酶的APAP葡萄糖醛酸化，还在3 'UTR区域确定了3个连锁的SNP，这些SNP由所有UGT 1A亚型共享，与人肝脏库中较高的APAP葡萄糖醛酸化相关。因此，在目的1中，我们提出通过研究蛋白质稳定性/定位、mRNA稳定性和翻译效率来阐明UGT 1A 6 cSNP和UGT 1A 3 '-UTR SNP对APAP葡萄糖醛酸化作用的分子机制。在目标2中，我们将确定这些UGT多态性和SULT和APAP基因中其他已知的功能多态性对接受治疗剂量APAP的志愿者中测量的APAP葡萄糖醛酸化、硫酸化和氧化速率的影响。我们还将确定APAP的代谢是否在非洲裔美国人与欧洲裔美国人相比是不同的（一个新的和未经检验的假设）。在目标3中，我们将利用来自2项正在进行的APAP诱导的肝毒性研究的DNA样本，以确定UGT、UGT和SULT多态性的这一经验证的子集是否可用于识别易发生APAP使用导致的肝毒性（过量或意外毒性）的患者。公共卫生相关性：我们的目标是确定一组遗传标记，可用于医生和患者指导他们选择安全有效的镇痛药物，并确定在APAP过量后进入急诊室的肝毒性高风险患者（需要特殊治疗）。

DESCRIPTION (provided by applicant): Acetaminophen (APAP) is the most commonly used medication in the United States but is also the most frequent cause of drug-induced hepatotoxicity. The long-term objective of this research is to elucidate the pharmacogenetic mechanisms that contribute to variability in individual risk for APAP-induced hepatotoxicity. Our working hypothesis is that genetic polymorphisms that modify the expression and function of enzymes and regulatory proteins involved in APAP toxification and detoxification can be used to identify individuals that have increased risk for APAP hepatotoxicity. The major focus of this work are genes encoding the enzymes that have been identified as critical to these pathways, including the UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and cytochromes P450 (CYPs). In preliminary work, we established UGT1A1, 1A6, and 1A9 as major APAP glucuronidation enzymes, and identified 3 linked amino acid polymorphisms in the UGT1A6 gene that alter APAP glucuronidation by recombinant enzyme, and also 3 linked SNPs in the 3'UTR region shared by all UGT1A isoforms that were associated with higher APAP glucuronidation in a human liver bank. Consequently, in Aim 1 we propose to elucidate the molecular mechanisms underlying the effects of the UGT1A6 cSNPs and the UGT1A 3'-UTR SNPs on APAP glucuronidation through studies of protein stability/localization, mRNA stability, and translation efficiency. In Aim 2 we will determine the effect of these UGT polymorphisms and other known functional polymorphisms in the SULT and CYP genes on rates of APAP glucuronidation, sulfation, and oxidation measured in volunteers that receive a therapeutic dose of APAP. We will also determine whether metabolism of APAP is different in African-Americans compared with European-Americans (a novel and untested hypothesis). In Aim 3 we will utilize DNA samples from 2 ongoing studies of APAP-induced hepatotoxicity to determine whether this validated subset of UGT, CYP, and SULT polymorphisms can be used to identify patients predisposed to developing hepatotoxicity resulting from APAP use (overdose or unintentional toxicity). Public health relevance: Our goal is to identify of a set of genetic markers that could be used by physicians and patients to guide their choice of safe and effective analgesic drugs, and identify patients admitted to an emergency room at high risk for hepatotoxicity (requiring special treatment) following an APAP overdose.