ROLE OF CYTOCHROMES P-450 GENES IN MUTAGENESIS AND CARCINOGENESIS

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The cytochrome P-450 supergene family codes for enzymes which metabolize a wide array of both xenobiotics including drugs and carcinogens, and endobiotics such as steroids and prostaglandins. In animals, multiple forms of these enzymes exhibiting broad and overlapping substrate specificities are expressed simultaneously, either constitutively or after administration of inducers. To define the contribution of a given cytochrome P-450 to the metabolism of specific drugs and carcinogens, it is important to express these enzymes individually in cells which lack endogenous background for these enzymes. Toward this goal we have begun to develop expression systems in which an individual cytochrome P-450 protein is synthesized from their coding DNA sequences. Success in this effort will enable us to define the contribution of each of these enzymes to mutagenesis and to cell transformation by chemical carcinogens. For this purpose, we have constructed infectious recombinant vaccinia virus and infectious recombinant retrovirus containing the full length coding cDNA sequences for mouse cytochrome P1-450 and P3-450. Human and mouse cells infected with the recombinant viruses expressed high levels of the authentic size proteins that were enzymatically active and displayed substrate specificities diagnostic of the respective enzymes. Preliminary experiments indicate that cytochrome P3-450 selectively activates heterocyclic arylamines and cytochrome P1-450 preferentially activates aromatic hydrocarbons; and this property appears to be mutually exclusive at limiting substrate concentrations. Furthermore, the cytochrome P3-450-activated food mutagens formed specific adducts with the DNA of cells expressing the P3-450. The DNA adducts detected were identical to those formed in mouse or rat liver after the in vivo administration of the food mutagens.