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Aryl and Alcohol Sulfotransferases in Drug Metabolism

药物代谢中的芳基和醇磺基转移酶

基本信息

批准号：
7874681
负责人：
MICHAEL W DUFFEL
金额：
$ 22.11万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7874681
关键词：
Address Alcohol sulfotransferase Alcohols Area Aromatic Amines Aromatic Polycyclic Hydrocarbons Binding Carcinogens Cell Respiration Cellular Structures Chemopreventive Agent Development Disulfides Environment Enzyme Inhibition Enzyme Kinetics Enzymes Estrogen Antagonists Estrogens Gene Expression Goals Human Hydroxylamine In Situ Individual Inorganic Sulfates Investigation Ions Isomerism Kinetics Knowledge Left Liver Mediating Metabolic Metabolic Activation Metabolic Biotransformation Metabolism Methodology Methods Modeling Molecular Oxidative Stress Oxides Pharmaceutical Preparations Play Protein Isoforms Public Health Quantitative Structure-Activity Relationship Rattus Recombinants Reduced Glutathione Regulation Research Role Slice Sulfhydryl Compounds Tamoxifen Tissues Unspecified or Sulfate Ion Sulfates Variant Work Xenobiotic Metabolism Xenobiotics antitumor agent base chemical carcinogen chemical carcinogenesis covalent bond cytotoxic design detoxication disulfide bond drug metabolism enantiomer functional group genotoxicity inhibitor/antagonist innovation insight macromolecule malignant breast neoplasm response sulfation sulfotransferase

项目摘要

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.

描述（由申请人提供）：磺基转移酶在许多药物的解毒以及许多化学致癌物的代谢活化中的作用越来越被认为是非常重要的。硫酸化作用是外源性物质代谢形成细胞毒性、致突变和/或致癌分子的关键组分，外源性物质包括源自烷基取代多环芳烃的苄醇、芳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磺基转移酶在外源性物质的细胞毒性、致突变和/或致癌作用中的作用，这些外源性物质具有或生物转化为含有苄醇、烯丙醇和N-羟基芳胺官能团的代谢物。为下一个项目期间提出的工作的主要目标是解决我们的知识的差距，这些磺基转移酶的催化功能的调节，通过基因表达和等位基因变异以外的手段。拟议的调查是基于中央的假设，即立体特异性识别的底物和抑制剂的芳基和醇磺基转移酶，这些酶的氧化环境，和动力学调节的共底物，PAPS，是关键的组成部分，在药物代谢和化学致癌作用的硫酸化率的预测。在即将到来的项目期间，研究的具体目标是：1）继续阐明来自他莫昔芬的烯丙基α-羟基化代谢物与大鼠STa和人SULT 2A 1醇磺基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浓度在大鼠和人醇磺基转移酶的催化调节中的作用，3）确定芳基和醇磺基转移酶中由二硫键形成引起的动力学变化的程度和意义，和4）开发基于定量结构-活性关系的芳基和醇磺基转移酶的异构体特异性抑制剂的设计方法。这项研究的结果将提供重要的新的洞察力的芳基和醇磺基转移酶的催化功能的动态调节机制，是重要的药物代谢和化学致癌作用，以及新的方法设计的异构体特异性抑制剂的磺基转移酶。因此，该项目与公共卫生高度相关，因为它提供了对硫酸化在药物代谢和外源性化学致癌物代谢中的作用的更多理解和预测。此外，具体目标#1对于理解和更准确地预测他莫昔芬的代谢具有额外的特定相关性，他莫昔芬是一种广泛使用的抗肿瘤剂和雌激素依赖性乳腺癌的化学预防剂。