This Program-Project Grant has as its goal and underlying them a better understanding of the biochemical and genetic mechanisms involved in the development of neoplasia induced by chemical carcinogens. Each of the projects is directed by one of the co-investigators of this grant, and each project will individually contribute to a greater under of an important aspect of the mechanisms in chemical carcinogenesis. While the individual projects are distinct, the interactions and sharing of specific expertise by the co-investigators serve to dramatically enhance the potential productivity of the group. Dr. Bradfield's group is involved in studying the genetic toxicology of the Ah locus and its interacting genes utilizing gene targeting technologies. Dr. Drinkwater is elucidating the genetic and hormonal factors involved in the stage of promotion during murine hepatocarcinogenesis. The objective of Dr. Fahl's research is to understand the mechanisms of the expression of specific glutathione S- transferase genes and their role in the resistance of cells to toxic and carcinogenic xenobiotics. Dr. Farnham's group is concerned with the role of the E2F family of transcription factors in the processes of liver regeneration and chemically-induced hepatocellular carcinogenesis in the mouse. Dr. Kasper seeks to understand structure-function relationships in specific members of the mixed-function oxidase system and to determine how individual components are related to xenobiotic metabolism and the overall function of the organism. Dr. Pitot's group has concerned itself primarily with an understanding of the biochemical and genetic mechanisms involved in the transition of hepatocytes from the stage of promotion to the stage of progression in the appearance of malignant neoplasia in rat liver. All of these projects will contribute to our knowledge of the chemical mediation of carcinogenesis. Extensive epidemiologic evidence has attested to the critical importance of the induction of cancer in the human by environmental and endogenous chemicals, e.g., smoking, diet, hormones, alcohol, and other drugs. Our ultimate understanding of the mechanisms by which such chemical induce cancer in the human is the long-term goal of the studies of this Program-Project Grant.