A concentration addition model for the activation of the constitutive androstane receptor by xenobiotic mixtures |
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Authors: | WS Baldwin JA Roling |
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Affiliation: | * Institute of Environmental Toxicology, Clemson University, Pendleton, South Carolina 29670 Biological Sciences, Bridgewater State College, Bridgewater, 02325 Massachusetts 1 To whom correspondence should be addressed at Clemson University, Inst of EnvironToxicology, Biological Sciences, 509 Westinghouse Rd., P.O. Box 709, Pendleton, SC 29670. Fax: 864-646-2277. E-mail: Baldwin{at}clemson.edu. |
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Abstract: | The effects of contaminants are typically studied in individualexposures; however, environmental exposures are rarely froma single contaminant. Therefore, the study of chemical mixturesis important in determining the effects of xenobiotics. Theconstitutive androstane receptor (CAR) responds to endobioticsand xenobiotics, and in turn induces detoxification enzymesinvolved in their elimination. First, we compared several androgensas inverse agonists, including androgens allegedly used by BayArea Laboratory Co-operative to enhance athletic performance.CAR inverse agonists ranked in order of potency were dihydroandrosterone(DHA) > tetrahydrogestrinone (THG) > androstanol >norbolethone. Therefore, we used DHA as an inverse agonist duringtransactivation assays. Next, we examined the effects of severalpesticides, plasticizers, steroids, and bile acids on CAR activation.Our data demonstrates that several pesticides and plasticizers,including diethylhexylphthalate, nonylphenol, cypermethrin,and chlorpyrifos activate CAR. Both full and partial CAR activatorswere discovered, and EC50 values and Hillslopes were determinedfor use in the concentration addition models. Concentrationaddition models with and without restraint values to accountfor partial activators were developed. Measured results fromtransactivation assays with a mixture of two to five chemicalsindicate that the concentration addition model without restraintscorrectly predicts activity unless all of the chemicals in themixture are partial activators, and then restraint values beconsidered. Overall, our data indicates that it is importantto consider that we are exposed to a milieu of chemicals, andthe efficacy of each individual chemical is not the sole factorin determining CAR's activity in mixture modeling. |
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Keywords: | CAR mixtures androgens. |
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