Acetaminophen Pharmacogenetics

说明(申请人提供)：扑热息痛(APAP)是美国最常用的药物，但也是药物引起肝毒性的最常见原因。这项研究的长期目标是阐明导致APAP诱导的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，改变APAP毒化和解毒过程中涉及的酶和调节蛋白的表达和功能的遗传多态可用于识别APAP肝毒性风险增加的个体。这项工作的主要焦点是编码对这些途径至关重要的酶的基因，包括UDP-葡萄糖醛酸基转移酶(UGTS)、磺基转移酶(SulfoTransfer Ase)和细胞色素P450(Cyps)。在前期工作中，我们确定了UGT1A1、1A6和1A9为主要的APAP葡萄糖醛酸化酶，并在UGT1A6基因中发现了3个连锁氨基酸的多态，它们通过重组酶改变了APAP的葡萄糖醛酸化作用，并在3‘UTR区发现了3个连锁SNPs，这3个SNP是所有UGT1a亚型所共有的，它们与人肝库中较高的APAP葡萄糖醛酸化水平相关。因此，在目标1中，我们建议通过蛋白质稳定性/定位、mRNA稳定性和翻译效率的研究来阐明UGT1A6cSNPs和UGT1A3‘-UTRSNPs影响APAP葡萄糖醛酸化的分子机制。在目标2中，我们将确定这些UGT多态以及sult和CYP基因中其他已知的功能多态对接受APAP治疗剂量的志愿者的APAP葡萄糖醛酸化、硫化和氧化率的影响。我们还将确定与欧洲裔美国人相比，非裔美国人的APAP代谢是否不同(一个新的、未经验证的假说)。在目标3中，我们将利用两项正在进行的APAP诱导的肝毒性研究的DNA样本来确定UGT、CYP和SULT的这种经过验证的亚型是否可以用于识别易因使用APAP而导致肝毒性(过量或无意毒性)的患者。公共卫生相关性：我们的目标是确定一套可供医生和患者使用的遗传标记，以指导他们选择安全有效的止痛药，并识别因APAP过量而被送入急诊室的肝毒性(需要特殊治疗)的高风险患者。

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.