Xenobiotic receptors mediate the response of organisms to their chemical environment. The general paradigm is that chemicals enter the cell and bind receptors leading to the activation of genes that encode enzymes that metabolize the chemical. This is a means to eliminate chemicals from the body. However in many cases, stimulation of xenobiotic receptors can lead to toxic and carcinogenic responses as a result of abnormal target gene activation. Several xenobitoic receptors are under study in the laboratory. These include 1) the aryl hydrocarbon receptor (AHR) and its heterodimerization partner ARNT that mediate the toxic response to dioxins and polyhalogenated hydrocarbons 2) the peroxisome proliferator activated receptors (PPAR) alpha, beta and gamma that are mainly involved in control of fatty acid metabolism and transport, 3) the farnesoid X receptor (FXR) that is responsible for control of bile acid metabolism and transport. The function of these receptors is being evaluated using gene knockout mice. Mice lacking the AHR are viable but are sick due to accelerated liver and other organ fibrosis. Studies with the AHR-null mice and cell lines derived from these mice have revealed a role for the AHR in cell cycle control. The ARNT knockout revealed that this protein is an obligate heterodimerization partner of the AHR and the hypoxia inducible factor HIF-1alpha. Hypoxia-inducible factor 1alpha (HNF-1alpha) conditional null mice have also been generated. Null mouse studies revealed that the PPARalpha is responsible for the toxic effects of peroxisome proliferators including hepatocarcinogenesis. These studies have led to hypothesis on the mechanism of action of peroxisome proliferators and the species differences in response to these chemicals that will be of great value to regulatory agencies. A PPARalpha-humanized mouse was produced that revealed that the receptor protein is responsible for the species differences in response to peroxisome proliferators. The humanized mice were resistant to peroxisome proliferators-induced cell proliferation and hepatocarcinogenesis as compared to wild-type mice expressing the corresponding mouse receptor. These data may explain the molecular basis for the resistance of humans to the hepatotoxic and carcinogenic effect of the PPARalpha ligand fibrate drugs. PPARbeta is involved in the immune response and in cell cycle control. Recent studies revealed a role for this receptor in modulating colon and skin carcinogenesis. Mice lacking expression of PPARbeta were resistant to both carcinogen-induced colon and skin cancer. PPARgamma is required for adipogenesis, control of macrophage function and is thought to be a cancer modifier gene. Studies using mice that are haploinsufficient in PPARgamma revealed that this receptor is protective against chemical carcinogen-induced cancers at the colon and other tissue sites. The FXR was found to control bile acid homeostasis and the enterohepatic flow of bile that is required for the elimination of many waste molecules from the body. Modulation of this receptor may offer a novel means to control cholesterol levels. Studies are underway to determine the role of FXR in atherosclerosis. Bile acids are also believed to be potent tumor promoters for colon carcinogenesis and thus this receptor may influence colon cancer susceptibility.
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