ARYL SULFORTRANSFERASE IN DRUG AND XENOBIOTIC METABOLISM

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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.