FUNCTION OF XENOBIOTIC RECEPTORS

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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 AHR trans-activates the CYP1A1, CYP1A2 and CYP1B1 genes and a number of other genes after complexing with 2,3 ,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 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. To determine the role of AHR in development and physiological homeostasis, and in the biological effect of dioxins, AHR-null mice were generated. The phenotypes observed in AHR-null mice suggest that the receptor has an important role in mammalian development and physiological homeostasis. The liver is clearly not normal in even younger null mice with evidence of fibrosis and altered hepatic architecture. In older animals, defects were detected in the cardiovascular system, including heart hypertrophy. The immune system was also affect by the loss of the AHR. The AHR-null mice were used to determine the role of the receptor in acute toxicity of TCDD. The null animals were resistant to the thymic toxicity and wasting syndrome associated with this notorious environmental contaminant. 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 o chemical carcinogenesis in an intact animal model, PPAR-alpha null mice were prepared and their phenotypes analyzed. These mice exhibited no phenotype suggesting an important role for the receptor in mammalian development. The null mice were completely resistant to all effects of peroxisome proliferators including induction of peroxisomes, target gene expression and hepatomegaly. Studies are in progress to determine the role of PPAR- alpha in the carcinogenic properties of peroxisome proliferators.