THE ROLE OF CYTOCHROME P-450 ENZYMES IN CARCINOGENESIS

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Microsomal cytochrome P-450s are a family of enzymes, some of which metabolize foreign compounds and chemical carcinogens. Some of these enzymes are inducible by carcinogenic compounds. For example, 3-methylcholanthrene induces cytochromes P1-450 and P3-450 in the mouse. These induced enzymes metabolize benzo(a)pyrene, aryl amines and other carcinogens. Some of the active metabolites formed bind to DNA and thus are presumed to initiate mutagenesis and carcinogenesis. We propose to express the cytochrome P1-450 and P3-450 enzymes in homologous and heterologous cells and determine the contribution of these enzymes to mutation and cell transformation. For this purpose, we have constructed infectious recombinant vaccinia viruses containing the full length cDNAs of P1-450 and P3-450. Human and mouse cells infected with the recombinant viruses showed high level expression of the authentic proteins as detected by immunoblotting. The expressed proteins are enzymatically active and exhibit distinguishable substrate specificities. We have also constructed recombinant retroviruses containing the cytochromes P1-450 and P3-450. Cells infected with these recombinants express cytochrome P3-450. Preliminary experiments indicate that the protein is enzymatically active. This system is now amiable to mutation and transformation analysis.