The PAH-induced or MC-induced P-450s are responsible for the metabolism of carcinogens, as well as a wide variety of both endogenous and exogenous compounds. The metabolism of carcinogens by PAh-induced P-450s can occur via pathways that contribute to their detoxification, or via pathways that convert these compounds to highly active carcinogenic species. However, several important questions about the process of chemical carcinogenesis and the metabolism of carcinogens by the P-450s remain to be answered. Many of these questions can be most effectively addressed through the analysis of the structure and regulation of the genes that encode the PAH-induced P-450s. The proposed research is designed to provide basic knowledge oif the structure and regulation of the P-450 genes. This knowledge combined with the cloned P-450 cDNAs and genes that will be generated during this project will provide tools required to assess the role of specific P-450 gene products in carcinogenesis, and to determine individual variation in susceptibility to cancer. The specific objectives of this research are to: Carry out the detailed structural analysis of two PAH-induced P-450 genes, that are available only in the PI's laboratory, and compare the structures of these genes to the published structures of other members of this gene family. Investigate other aspects of P-450 gene structure that will yield information for the analysis of P-450 gene regulation and for investigating the roles of specific P-450 gene products in carcinogenesis Study the roles that modulation of transcription, mRNA stabilization and mRNA processing play in regulating P-450c, P-450d and P-450m mRNA levels in vivo and in a cultured hepatocyte cell line Use DNA-mediated gene transfer of cloned P-450 genes, gene fragments and gene hybrids to locate sequences that take part in the control of P-450c, P-450d and P-450m gene expression.
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