Tow major goals of drug metabolism studies ar 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 uses minor changes to the chemical structure of various drugs to alter their metabolism, and thereby modify their toxicity or therapeutic activity. Thus, the application is an extension of our previous work to elucidate molecular mechanisms of reactive. Thus, the application is an extension of our previous work to elucidate molecular mechanisms of reactive metabolite formation and disposition, to characterize mechanism of oxidative N-dealkylation, and to synthesize suicide inhibitors of aromatase.
The aims of the present project are: 1. To use dimethylated and regioisomeric analogs of the widely used analgesic and antipyretic, acetaminophen, to determien the role of oxidative stress and arylation of tissue proteins in hepatotoxicity caused by the drug. A combination of radiochemical and immunochemical techniques coupled with 2-D electrophoresis and enzyme activity assays will be used as tools to help dissect the mechanisms. 2. To characterize the metabolism and toxicity of R-(+)-pulegone and its proximate toxin, menthofuran, by modulation of thiol status and by oxygen-18 labeling techniques. 3. To determien the contribution of electronic and steric effects in cytochrome P-450-mediated carbinolamine formation form N- methylcarbazole by synthesizing and testing a series of dideuterated N-methylcarbazoles that either electronically or sterically modify the N-methyl group. 4. To determine the selectivity of thioandrogens for aromatase by investigating the effects of thiol group modification of androgens on cytochromes P-450 other than aromatase, and to investigate the molecular mechanism of inactivation of aromatase itself by the use of radiolabeled thioandrogens and sulfenic acid and/or peroxyandrogen metabolite probes. The overall project is expected to advance our knowledge of mechanisms of drug-induced cell death and mechanisms of metabolite formation, and may lead to drugs with enhanced therapeutic benefit.
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