FUNCTION OF P450S AND XENOBIOTIC RECEPTORS

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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 and they are known to be involved in metabolism of most therapeutically-used agents. The P450s are also critical in the metabolic-activation of promutagens and procarcinogens. P450s known to metabolize xenobiotics are found in the CYP1, CYP2 and CYP3 families. Each of these families consist of two or more subfamilies containing the individual P450 forms. One question that has not been directly addressed is whether P450s are required for chemical carcinogenesis in an intact animal. The fact that P450s can metabolically-activate procarcinogens implies that they are involved in the process of chemical carcinogenesis. However, 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. However, no direct evidence is available to establish that P450s are necessary for carcinogenesis in an intact animal model system. P450s and other enzymes are under control of ligand-dependent transcription factors that interact with xenobiotics. The most well studied is the dioxin or Ah receptor that is composed of two heterodimeric subunits consisting of a ligand binding subunit (AHR) and a subunit called the Ah receptor nuclear translocator (Arnt). This receptor trans-activates the CYP1A1, CYP1A2 and CYP1B1 genes and a number of other genes after complexing with 2,3,7,8- tetrachlorodibenzo-p-dioxin or polycyclic aromatic hydrocarbon inducers. The physiological function of the Ah receptor, if any, is currently unknown, as is the existence of an endogenous ligand. A structurally- diverse class of chemicals called peroxisome proliferators also interact with a family of receptors that are in the steroid receptor superfamily. Three subunits are found in frogs and mammals, designated PPAR-alpha, PPAR-beta and PPAR-gamma. The alpha form is most abundantly expressed in liver and its participation in regulating fatty acid catabolism has been demonstrated. A number of peroxisome proliferators or potential ligands for PPAR-alpha, are also rodent hepatocarcinogens. This fact is of concern to regulatory agencies since hyperlipidemics, leukotriene antagonists and other drugs are peroxisome proliferators and are used in humans. To determine the physiological roles of xenobiotic receptors and P450s and their participation in the process of chemical carcinogenesis in an intact animal model, gene knockout mice were prepared and their phenotypes analyzed.