Aryl and Alcohol Sulfotransferases in Drug Metabolism

描述（由申请人提供）：磺胺转移酶在许多药物的解毒以及许多化学致癌物的代谢激活中的作用越来越被认为是非常重要的。磺化是代谢形成细胞毒性、致突变和/或致癌分子的关键组成部分，这些分子来自于由烷基取代的多环芳烃衍生的苯基醇、芳香胺和硝基芳烃的羟胺代谢物以及烯丙醇。本研究的长期目标是更全面地了解和预测芳基和醇基硫转移酶在具有或被生物转化为含有苯基醇、烯丙醇和n -羟基芳基胺官能团的代谢物的异种生物的细胞毒性、致突变性和/或致癌性作用中的作用。下一个项目期间提出的工作的主要目标是通过基因表达和等位基因变异以外的手段解决我们对这些硫转移酶催化功能调节的知识空白。这项研究的核心假设是，芳基和醇基硫转移酶识别底物和抑制剂的立体特异性、这些酶的氧化环境以及共底物PAPS的动力学调节是预测药物代谢和化学致癌过程中硫酸化速率的关键组成部分。在即将开展的项目期间，研究的具体目标是：1)继续阐明他莫昔芬衍生的烯丙基α -羟化代谢物与大鼠STa和人SULT2A1醇硫转移酶相互作用的立体选择性，并研究他莫昔芬及其代谢物对这些酶的抑制作用；2)确定PAPS浓度在大鼠和人醇硫转移酶的催化调节中的作用。3)确定芳基和醇基硫转移酶中二硫键形成引起的动力学变化的程度和意义；4)基于定量构效关系开发芳基和醇基硫转移酶的异构体特异性抑制剂的设计方法。本研究结果将对药物代谢和化学致癌作用中重要的芳基和醇基硫转移酶催化功能的动态调控机制提供重要的新见解，并为设计硫转移酶的异构体特异性抑制剂提供新的方法。因此，该项目与公共卫生高度相关，因为它增加了对磺化在药物代谢和外源物对化学致癌物代谢中的作用的理解和预测。此外，特异性目标#1与理解和更准确地预测他莫昔芬（一种广泛用于雌激素依赖性乳腺癌的抗肿瘤剂和化学预防剂）的代谢有额外的特殊关系。

DESCRIPTION (provided by applicant): The roles of sulfotransferases in detoxication of many drugs, as well as in the metabolic activation of many chemical carcinogens, are increasingly recognized as highly significant. Sulfation is a key component in the metabolic formation of cytotoxic, mutagenic and/or carcinogenic molecules from xenobiotics that include benzylic alcohols derived from alkyl-substituted polycyclic aromatic hydrocarbons, hydroxylamine metabolites of aromatic amines and nitroaromatics, and allylic alcohols. The long-term goal of this research is to more fully understand and predict the roles that aryl and alcohol sulfotransferases play in the cytotoxic, mutagenic, and/or carcinogenic effects of xenobiotics that either possess or are biotransformed into metabolites containing benzylic alcohol, allylic alcohol, and N-hydroxy arylamine functional groups. The primary objective of the work proposed for the next project period is to address the gaps in our knowledge of the regulation of the catalytic function of these sulfotransferases by means other than gene expression and allelic variations. The proposed investigation is based on the central hypothesis that stereospecificity in recognition of substrates and inhibitors by aryl and alcohol sulfotransferases, the oxidative environment of these enzymes, and kinetic regulation by the co-substrate, PAPS, are critical components in the prediction of the rates of sulfation in drug metabolism and chemical carcinogenesis. The specific aims of the research during the upcoming project period are to 1) continue elucidation of the stereoselectivity of interactions of allylic alpha-hydroxylated metabolites derived from Tamoxifen with rat STa and human SULT2A1 alcohol sulfotransferases and study the inhibition of these enzymes by Tamoxifen and its metabolites, 2) determine the role of the concentration of PAPS in the catalytic regulation of rat and human alcohol sulfotransferases, 3) determine the extent and significance of changes in kinetics resulting from disulfide bond formation in aryl and alcohol sulfotransferases, and 4) develop methods for design of isoform-specific inhibitors of aryl and alcohol sulfotransferases based on quantitative structure-activity relationships. The results of this research will provide significant new insight into the mechanisms for dynamic regulation of the catalytic function of aryl and alcohol sulfotransferases that are important to drug metabolism and chemical carcinogenesis as well as new methodology for the design of isoform-specific inhibitors of sulfotransferases. Thus, this project is highly relevant to public health due to its provision of increased understanding and prediction of the roles of sulfation both in drug metabolism and in the metabolism of xenobiotics to chemical carcinogens. Moreover, specific aim #1 has additional particular relevance to understanding and more accurately predicting the metabolism of Tamoxifen, a widely used antitumor agent and chemopreventive agent for estrogen-dependent breast cancer.