STUDIES ON THE ACTIVE SITES OF CYTOCHROMES P-450

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The cytochrome P-450 enzymes are a family of monooxygenases responsible for the oxidation of a wide variety of endogenous and exogenous compounds. The broad substrate specificities and diverse mechanisms of oxidation of these isozymes makes it difficult to predict the pathways involved in the metabolism of a given compound. It can be rationalized that the regio-specificity of metabolism for a given enzyme-substrate complex is a function of two factors: 1) the orientation(s) of the substrate in the enzymes active site of the isozyme, and 2) the tendency of the substrates functional groups toward oxidation. An understanding of both of these factors for each isozyme together with knowledge of the amounts of each isozyme present, are necessary for predictions in drug metabolism. These studies are in progress to probe these two factors and their interaction: 1) studies of the cytochrome P-450a active sites. 2) theoretical and experimental studies on the oxidation of functional groups and 3) theoretical and experimental studies on the mechanism of aromatase oxidations.