FUNCTION OF CYTOCHROMES P450

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In mammals, a large number of enzymes exist that metabolize drugs and other xenobiotics. Cytochrome P450s are among the most important of these enzymes that are involved in metabolism of most therapeutically- used drugs. In addition, P450s catalyze the metabolic-activation of chemical carcinogens. The P450s involved in xenobiotic metabolism are found in the CYP1, CYP2 and CYP3 families. Each of these families consist of two or more subfamilies. The fact that P450s can metabolically-activate toxins and procarcinogens in vitro implies that they are involved in toxicity's and cancer. However, it is not known whether P450s are required for the toxicity and carcinogenicity of chemicals in an intact animal. The only experiments suggestive of a role for P450s in cancer etiology are indirect chemically-induced transformation assays in cell culture, and genetic experiments in mice involving the Ah locus. No direct evidence is available to establish that P450s are necessary for carcinogenesis in an intact animal model system. To assess the potential contribution of P450s to acute chemical toxicity's and the process of chemical carcinogenesis, and to determine their roles, if any, in mammalian development and physiological homeostasis, P450-null mice were produced. P450s were selected for analysis based on their conservation of activities between mice and humans. CYP1A2, that is capable of metabolic activation of arylamine and heterocyclic amine carcinogens and CYP2E1, P450s that metabolizes a large number of low molecular weight toxins and cancer suspect chemicals were selected for analysis. CYP1A2 and CYP2E1-null mice were produced and found to be indistinguishable from wild-type mice having the P450s, indicating that they have no critical role in mammalian development or physiological homeostasis. Acute toxicity's studies revealed that CYP2E1-null mice mediate the hepatotoxic effects of the common analgesic acetaminophen and the genotoxicity found after benzene administration. These studies indicate that under condition conditions of acute chemical exposures, P450s are required for toxicity's. Studies are in progress to determine whether P450s are necessary for carcinogenesis in the neonatal mouse carcinogen bioassay.