The activation of certain caricnogens and anticancer agents to their cytoactive metabolites is catalyzed by the cytochrome P-450 dependent mixed function oxidase system. The goals of this proposal are to define the presence and functionality of this system in the human large bowel; to identify specific form or forms of cytochrome P-450 involved in the metabolism of dimethylhydrazine (organ-specific model colon carcinogen) and cyclophosphamide (an anticancer agent requiring cytochrome P-450 for activation recently shown to be effective in killing human colon tumor cells in culture); and to determine factors which regulate the activity of the cytochrome P-450 system in human colon. Pursuit of these goals will involve the identification of the forms of cytochrome P-450 in human colon and human colon tumors. We will employ both immunochemical identification techniques (e.g., Western blot) and standard purification techniques to define the P-450 constituency of the human large bowel and colonic tumors. Using antibodies and other inhibitor and inducers will identify specific forms catalyzing activation of carcinogens and/or chemotherapeutic agents. In these ways we will test the hypothesis that the cytochrome P-450 system activates carcinogens and anticancer agents in the human colon thereby playing a role in carcinogenesis and chemotherapy.
