Identification of chemical modulators of the constitutive activated receptor (CAR) in a gene expression compendium.

Content Provider	Europe PMC
Author	Oshida, Keiyu Vasani, Naresh Jones, Carlton Moore, Tanya Hester, Susan Nesnow, Stephen Auerbach, Scott Geter, David R. Aleksunes, Lauren M. Thomas, Russell S. Applegate, Dawn Klaassen, Curtis D. Corton, J. Christopher
Copyright Year	2015
Description	The nuclear receptor family member constitutive activated receptor (CAR) is activated by structurally diverse drugs and environmentally-relevant chemicals leading to transcriptional regulation of genes involved in xenobiotic metabolism and transport. Chronic activation of CAR increases liver cancer incidence in rodents, whereas suppression of CAR can lead to steatosis and insulin insensitivity. Here, analytical methods were developed to screen for chemical treatments in a gene expression compendium that lead to alteration of CAR activity. A gene expression biomarker signature of 83 CAR-dependent genes was identified using microarray profiles from the livers of wild-type and CAR-null mice after exposure to three structurally-diverse CAR activators (CITCO, phenobarbital, TCPOBOP). A rank-based algorithm (Running Fisher’s algorithm (p-value ≤ 10-4)) was used to evaluate the similarity between the CAR biomarker signature and a test set of 28 and 32 comparisons positive or negative, respectively, for CAR activation; the test resulted in a balanced accuracy of 97%. The biomarker signature was used to identify chemicals that activate or suppress CAR in an annotated mouse liver/primary hepatocyte gene expression database of ~1850 comparisons. CAR was activated by 1) activators of the aryl hydrocarbon receptor (AhR) in wild-type but not AhR-null mice, 2) pregnane X receptor (PXR) activators in wild-type and to lesser extents in PXR-null mice, and 3) activators of PPARα in wild-type and PPARα-null mice. CAR was consistently activated by five conazole fungicides and four perfluorinated compounds. Comparison of effects in wild-type and CAR-null mice showed that the fungicide propiconazole increased liver weight and hepatocyte proliferation in a CAR-dependent manner, whereas the perfluorinated compound perfluorooctanoic acid (PFOA) increased these endpoints in a CAR-independent manner. A number of compounds suppressed CAR coincident with increases in markers of inflammation including acetaminophen, concanavalin A, lipopolysaccharide, and 300 nm silica particles. In conclusion, we have shown that a CAR biomarker signature coupled with a rank-based similarity method accurately predicts CAR activation. This analytical approach, when applied to a gene expression compendium, increased the universe of known chemicals that directly or indirectly activate CAR, highlighting the promiscuous nature of CAR activation and signaling through activation of other xenobiotic-activated receptors.
Abstract	The nuclear receptor family member constitutive activated receptor (CAR) isactivated by structurally diverse drugs and environmentally-relevant chemicalsleading to transcriptional regulation of genes involved in xenobiotic metabolismand transport. Chronic activation of CAR increases liver cancer incidence inrodents, whereas suppression of CAR can lead to steatosis and insulininsensitivity. Here, analytical methods were developed to screen for chemicaltreatments in a gene expression compendium that lead to alteration of CARactivity. A gene expression biomarker signature of 83 CAR-dependent genes wasidentified using microarray profiles from the livers of wild-type and CAR-nullmice after exposure to three structurally-diverse CAR activators (CITCO,phenobarbital, TCPOBOP). A rank-based algorithm (Running Fisher’salgorithm (p-value ≤ 10-4)) was used to evaluate thesimilarity between the CAR biomarker signature and a test set of 28 and 32comparisons positive or negative, respectively, for CAR activation; the testresulted in a balanced accuracy of 97%. The biomarker signature was used toidentify chemicals that activate or suppress CAR in an annotated mouseliver/primary hepatocyte gene expression database of ~1850 comparisons. CAR wasactivated by 1) activators of the aryl hydrocarbon receptor (AhR) in wild-typebut not AhR-null mice, 2) pregnane X receptor (PXR) activators in wild-type andto lesser extents in PXR-null mice, and 3) activators of PPARα inwild-type and PPARα-null mice. CAR was consistently activated by fiveconazole fungicides and four perfluorinated compounds. Comparison of effects inwild-type and CAR-null mice showed that the fungicide propiconazole increasedliver weight and hepatocyte proliferation in a CAR-dependent manner, whereas theperfluorinated compound perfluorooctanoic acid (PFOA) increased these endpointsin a CAR-independent manner. A number of compounds suppressed CAR coincidentwith increases in markers of inflammation including acetaminophen, concanavalinA, lipopolysaccharide, and 300 nm silica particles. In conclusion, we have shownthat a CAR biomarker signature coupled with a rank-based similarity methodaccurately predicts CAR activation. This analytical approach, when applied to agene expression compendium, increased the universe of known chemicals thatdirectly or indirectly activate CAR, highlighting the promiscuous nature of CARactivation and signaling through activation of other xenobiotic-activatedreceptors.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4422105&blobtype=pdf
Volume Number	13
DOI	10.1621/nrs.13002
PubMed Central reference number	PMC4422105
PubMed reference number	25949234
Journal	Nuclear Receptor Signaling [Nucl Recept Signal]
e-ISSN	15507629
Language	English
Publisher	Nuclear Receptor Signaling Atlas
Publisher Date	2015-04-27
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited. Copyright © 2015, Oshida et al.
Subject Keyword	constitutive activated receptor transcript profiling liver cancer metabolic syndrome steatosis conazoles perfluorinated compounds aryl hydrocarbon receptor pregnane X receptor peroxisome proliferator-activated receptor
Content Type	Text
Resource Type	Article
Subject	Medicine