ARYL SULFORTRANSFERASE IN DRUG AND XENOBIOTIC METABOLISM

本申请中提出的研究针对的是衬底 大鼠肝脏芳基转移酶IV(AST IV)的特异性 通过使用模型化合物提供基本见解的系统观点 转化为决定催化效率的分子参数。这 调查将集中在AST IV上，因为它是主要的芳基 大鼠肝脏中的磺基转移酶，其活性与芳基异羟肟酸和 苄基醇类。这些官能团存在于或存在于 由多种药物和其他外源物质代谢而成， 包括许多心血管药物、肾上腺素能药物、止痛药和 抗抑郁药。芳基异羟肟酸和苯甲酸酯的硫酸酯 酒精通常是反应性的，并与各种 细胞毒性。本研究将阐明天冬氨酸转氨酶IV在 芳基异羟肟酸和苯甲醇的硫酸盐化反应模型 研究电子、立体和立体化学因素的化合物 在纯化的AST IV的特异性上。此外，模型化合物将 用于定量测定N-O-硫酸盐的反应性 与亲核试剂的共轭物和苯硫酸盐。 因为大多数芳基异羟肟酸和苄基醇通常形成 在体内细胞色素P-450单加氧酶的影响下，它也是 重要的是要知道AST IV是否存在于相同的肝细胞中 细胞色素P-450。因此，将使用免疫组织化学技术 探讨AST IV在大鼠肺小叶内的定位和分布 老鼠肝。还将进行研究，以评估总体变化 肝组织中AST IV的含量及其在肝内的分布 使大鼠暴露在各种诱导剂中。其他关于中国的研究 抑制物对AST IV活性的调节也将进行。 天冬氨酸氨基转移酶IV基因的特异性、定位和调控研究 细胞色素P-450单加氧酶的补充研究已经完成。 这些研究的结果将极大地推动我们的 对AST IV与其他药物代谢关系的认识 酶，在化学和形态上都是如此。归根结底， 这项研究的结果将为预测 新药或更复杂药物的代谢和药理学。

The research proposed in this application addresses the substrate specificity of rat liver aryl sulfotransferase IV (AST IV) from a systematic viewpoint by using model compounds to give fundamental insight into molecular parameters which determine catalytic efficiency. This investigation will focus on AST IV, since it is the major aryl sulfotransferase in rat liver which is active with arylhydroxamic acids and benzylic alcohols. These functional groups either are present in or are formed metabolically from a wide variety of drugs and other xenobiotics, including many cardiovascular drugs, adrenergic agents, analgesics, and antidepressants. The sulfate esters of arylhydroxamic acids and benzylic alcohols are often reactive, and are implicated in a variety of cytotoxicities. This research will elucidate the role of AST IV in sulfation of arylhydroxamic acids and benzyl alcohols by using model compounds to study electronic, steric, and stereochemical factors involved in the specificity of purified AST IV. Furthermore, model compounds will be used to quantitatively determine the reactivity of the N-O-sulfate conjugates and benzylic sulfates with nucleophiles. Since most arylhydroxamic acids and benzylic alcohols are normally formed in vivo under the influence of cytochrome P-450 monooxygenases, it is also important to know if AST IV is present in the same liver cells as are the cytochromes P-450. Therefore, immunohistochemical techniques will be used to determine the intralobular localization and distribution of AST IV in rat liver. Studies will also be conducted to evaluate changes in total hepatic content and in intrahepatic distribution of AST IV following exposure of rats to various inducing agents. Other studies on the regulation of AST IV activity by inhibitors will also be conducted. Investigations on specificity, localization, and regulation of AST IV will complement studies already completed on cytochrome P-450 monooxygenases. Results to be forthcoming from these studies will greatly advance our knowledge of the relationship between AST IV and other drug metabolizing enzymes, both on a chemical and morphological level. Ultimately, the results of this research will form a firm basis for predicting the metabolism and pharmacology of new or more complex drugs.