FUNCTION OF XENOBIOTIC RECEPTORS

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The Ah receptor (AHR) trans-activates the CYP1A1, CYP1A2 and CYP1B1 genes and a number of other target genes after complexing with dioxins or polycyclic aromatic hydrocarbon. It is beleived to mediate the toxic and carcinogenic effects of these chemicals. The physiological function of the AHR 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 with evidence of fibrosis and altered hepatic architecture. Hepatic contents of retinoic acid (RA) and its major storage product, retinyl palmitate were found to be markedly elevated in the AHR-null compared to wild-type mice. An increase in retinoic acid-responsive genes was also noted. Low levels of RA metabolism was also found indicating that a cytochrome P450 responsible for RA catabolism is under control of the AHR. Altered RA levels may cause the fibrosis found in liver and other organs. 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 role regulating enzymes involved in 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 humans are exposed to hyperlipidemic drugs, plasticizers used in the chemical industry, the degreasing agent trichloroethylene and other chemicals exhibiting peroxisome proliferation activity and hepatocarcinogenesis potential in rodent model systems. To address the physiological role of PPAR-alpha and its role in the toxic and carcinogenic effects of peroxisome proliferators, PPAR-alpha-null mice were produced. A carcinogenesis bioassay using the potent experimental peroxisome proliferator Wy-14,643 revealed that PPAR-null mice were resistant to hepatocarcinogenesis indicating that the receptor mediates the mechanism of action of the non-genotoxic carcinogen peroxisome proliferators. PPAR-null mice were also found to be resistant to many, but not all of the toxicity's found in wild-type mice exposed to the plasticizer di(2-ethylhehyl)phthalate.