Most chemicals of environmental and industrial concern are neither inherently toxic nor carcinogenic but are activated to highly reactive toxic and carcinogenic metabolites by a family of hemoproteins collectively known as the cytochrome P-450 system. The applicant's long-term goal is to characterize the profile of cytochrome P-450 isozymes in hepatic and extrahepatic tissues and to determine the dual role of these isozymes in the metabolism of toxic xenobiotics (such as chemical carcinogens, environmental pollutants and drugs) and endogenous substrates (such as steroids, vitamins and fatty acids). The importance of this long-term goal is two-fold. First, it will help establish the extent to which differences between cytochrome P-450 systems is the molecular basis for organ- and species-selective toxicity and carcinogenicity. This is important in understanding the individuality of human response to toxic chemicals and carcinogens. Second, it will help delineate the relationship between those forms of cytochrome P-450 that metabolize xenobiotics and those that metabolize endogenous substrates. This is important in understanding the interactions between foreign chemicals and endogenous substances.
The specific aims of this application are to determine the presence and inducibility of cytochromes P-450a - P-450e (or enzymes immunochemically related to these five rat liver microsomal isozymes) in extrahepatic microsomes from rats and in liver microsomes from other laboratory animals by immunochemical analysis and by analysis of testosterone metabolism. In addition to being the most sensitive method, immunochemical analysis is the only method of specifically measuring an individual form of cytochrome P-450 in a mixture of isozymes. An HPLC system capable of resolving 18 potential metabolites of testosterone is a new method of probing the cytochrome P-450 isozymes in a tissue, which exploits the unusually high degree of regio- and stereospecificity with which individual isozymes metabolize testosterone. This particular choice of methods for studying the profile of cytochrome P-450 isozymes in tissues provides a unique opportunity to establish if certain xenobiotic-metabolizing forms of cytochrome P-450 perform a physiologic function (namely androgen deactivation and/or activation) and if specific pathways of testosterone metabolism have potential value as non-invasive methods of probing the profile of cytochrome P-450 isozymes in man. Addressing such issues serves to broaden the significance of the proposed study, and directs the applicant's long-term goals towards human aspects of toxicology and cancer.
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