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 and the process of chemical carcinogenesis, and to determine their roles, if any, in mammalian development and physiological homeostasis, P450-null mice were produced. Recent studies have revealed that CYP1B1-null mice have no phenotype indicating that this well conserved P450 is not required for mammalian development or physiological homeostasis. A carcinogen bioassay using the experimental polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) revealed that CYP1B1 is required for lymphomagenesis and skin cancers caused by this agent. These studies establish a critical role of CYP1B1 in forming the 3,4-epoxide of DMBA that leads to the ultimate carcinogenic metabolite, DMBA-3,4-diol,1,2-epoxide. Mice lacking other critical xenobiotic-metabolizing enzymes have also been produced. Microsomal epoxide hydrolase (mEH) null mice were made and found to have no deleterious phenotype further establishing that most of the xenobiotic-metabolizing enzymes are not critical for development and physiological homeostasis. Similar to the CYP1B1-null mice, the mEH-null animals are considerably less susceptable to DMBA-induced skin cancer thus confirming the role of mEH in production of the diol-epoxide ultimate carcinogenic metabolite of polycyclic aromatic hydrocarbons.
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