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A Global Genomic Screening Strategy Reveals Diverse Activators of Constitutive Activated Receptor (CAR)
Citation:
Oshida, K., N. Vasani, B. Chorley, S. Hester, W. Ward, R. Thomas, D. Applegate, L. Alexsunes, C. Klaassen, AND C. Corton. A Global Genomic Screening Strategy Reveals Diverse Activators of Constitutive Activated Receptor (CAR). Presented at Society of Toxicology Annual Meeting, March 10 - 14, 2013.
Impact/Purpose:
This abstract is for presentation at the Society of Toxicology meeting, March 10-14, 2013, San Antonio, TX
Description:
A comprehensive survey of conditions that activate CAR in the mouse liver has not been carried out but would be useful in understanding their impact on CAR-dependent liver tumor induction. A gene signature dependent on CAR activation was identified by comparing the transcript profiles after exposure to three CAR activators (phenobarbitaL TCPOBOP, CITCO) in wild-type and CAR-null mice. In independent experiments using transcript profiles from the livers of chemically-exposed male or female mice, the signature correctly predlicted activation of 3 CAR activators but not 9 activators of other pathways. The signature was used with 5 classification methods (e.g., support vector machines, K-nearest neighbors) to identify conditions in which CAR was activated in an Affymetrix compendium of ~750 mouse liver transcript comparisons encompassing a broad range of chemical, dietary and genetic perturbations. We found that CAR is activated by a large number of chemicals, dietary regimens and genetic mutations. Specific and novel findings include activation by 1) two PXR activators in a PXR-dependent manner indicating crosstalk between CAR and PXR, 2) 12 out of 15 chemical and triglyceride activators of PPARalpha to greater levels in PPARalpha-null mice than in wild type mice indicating that most PPARalpha activators are also CAR activators and there exists antagonism between CAR and PPARalpha, and 3) null mutations in a number of transcription factors (AhR, Fxr, Hnfla, Pxr) that control expression of genes involved in metabolism of exogenous and endogenous chemicals. The findings increase our understanding of the factors that impact CAR activation and that could contribute to increases in CAR-dependent liver tumors. This abstract does not represent EPA policy.