Two major goals of drug metabolism studies are to identify and characterize pathways of biotransformation that lead to toxic and active metabolites, and to utilize this information to therapeutic advantage. The research described in this proposal aims to use minor modifications to the chemical structure of various drugs to alter their metabolism, and thereby modify toxicity or therapeutic activity. Dimethylated analogs and regioisomers of the widely used mild analgesic-antipyretic drug, acetaminophen, will be synthesized in order to better characterize mechanisms of hepatocellular toxicity caused by acetaminophen. Some of these analogs have rather unique chemical and toxicological properties, and will be used to determine if covalent binding of metabolites to particular cellular proteins is important to their cytotoxic activity. In similar studies, structural analogs of a toxic monoterpene flavoring and fragrance agent, R-(+)-pulegone, will be used to investigate its mode of cytotoxicity. Specific deuterium labeling will aid in both this study, and specific deuterium and tritium labeling of N-methylcarbazole will be used to determine intrinsic isotope effects in carbinolamine formation. Carbinolamines are important intermediates in oxidative N-dealkylation, a major route of metabolism for many drugs. Finally, sulfhydryl groups will be incorporated into specific sites of male sex hormones, the androgens. This structural modification is anticipated to lead to reactive metabolite formation in their conversion by the enzyme, aromatase, to the female sex hormones, the estrogens. During this metabolism suicide inactivation of the enzyme is expected to occur. Such an effect may be of therapeutic utility in controlling the growth of estrogen-dependent tumors. Thus, minor structural modifications will aid in our understanding of mechanisms of drug-induced cell death and mechanisms of metabolite formation, and they may lead to drugs with therapeutic benefit.
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