Skin is the largest body organ and functions as a major direct interface between the body and the environment and is therefore exposed throughout life to a variety of chemical and physical agents. Traditionally it was thought that the skin was an inert structural barrier whose major function was protective. In the past decade or so it has become clear that the skin is, in fact, a vigorously active site of drug and chemical metabolism. Such metabolic activity may be critical to the detoxification of exogenous chemicals or conversely this enzyme activity may be a determinant of toxic responses such as carcinogenesis. It is proposed to continue our studies using neonatal rodent skin as an experimental model system. In addition it is planned to utilize newer in vitro cell culture (keratinocyte) and organ culture (epidermal) techniques with which to assess xenobiotic metabolism in human skin. It is planned to conduct studies to more fully characterize the cytochrome P-450-dependent monooxygenases in mammalian skin and in epidermis. The possible role of this enzyme system in the metabolic transformation of endogenous leukotrienes, which are important mediators of inflammation, will be studied. Keratinocyte cell cultures (rodent and human) and human organ culture systems will be employed to study xenobiotic metabolism in the epidermis. Enzyme activity, enzyme-mediated binding of polyaromatic hydrocarbon carcinogens to DNA and patterns of carcinogen metabolism will be defined. Carcinogen-DNA adducts will be sought in rodent and human epidermis using highly specific monoclonal antibodies directed against benzo-[a]pyrene-DNA adducts and an enzyme-linked immunoabsorbant assay. The ability of membrane-bound enzyme preparations from the epidermis to enhance the mutagenicity of selected known skin carcinogens will be assessed. Both prokaryotic and eukaryotic assay systems will be employed. It is also planned to evaluate the mechanism of action of two potentially important classes of inhibitors of polyaromatic hydrocarbon carcinogenesis. The polyphenol, ellagic acid, and the imidazole compound, clotrimazole, will be utilized as prototypes. The long-range goal of these studies is to define the metabolic responsiveness of skin to environmental chemicals and to devise strategies that reduce toxic risks that result from such exposures.
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