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Research ArticleArticle

Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes

Elizabeth A. Rondini, Zofia Duniec-Dmuchowski and Thomas A. Kocarek
Drug Metabolism and Disposition April 2016, 44 (4) 595-604; DOI: https://doi.org/10.1124/dmd.115.068551
Elizabeth A. Rondini
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan
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Zofia Duniec-Dmuchowski
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan
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Thomas A. Kocarek
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan
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Abstract

Our laboratory previously reported that accumulation of nonsterol isoprenoids following treatment with the squalene synthase inhibitor, squalestatin 1 (SQ1) markedly induced cytochrome P450 (CYP)2B1 mRNA and reporter activity in primary cultured rat hepatocytes, which was dependent on activation of the constitutive androstane receptor (CAR). The objective of the current study was to evaluate whether isoprenoids likewise activate murine CAR (mCAR) or one or more isoforms of human CAR (hCAR) produced by alternative splicing (SPTV, hCAR2; APYLT, hCAR3). We found that SQ1 significantly induced Cyp2b10 mRNA (∼3.5-fold) in primary hepatocytes isolated from both CAR–wild-type and humanized CAR transgenic mice, whereas the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin had no effect. In the absence of CAR, basal Cyp2b10 mRNA levels were reduced by 28-fold and the effect of SQ1 on Cyp2b10 induction was attenuated. Cotransfection with an expression plasmid for hCAR1, but not hCAR2 or hCAR3, mediated SQ1-induced CYP2B1 and CYP2B6 reporter activation in hepatocytes isolated from CAR-knockout mice. This effect was also observed following treatment with the isoprenoid trans,trans-farnesol. The direct agonist CITCO increased interaction of hCAR1, hCAR2, and hCAR3 with steroid receptor coactivator-1. However, no significant effect on coactivator recruitment was observed with SQ1, suggesting an indirect activation mechanism. Further results from an in vitro ligand binding assay demonstrated that neither farnesol nor other isoprenoids are direct ligands for hCAR1. Collectively, our findings demonstrate that SQ1 activates CYP2B transcriptional responses through farnesol metabolism in an hCAR1-dependent manner. Further, this effect probably occurs through an indirect mechanism.

Footnotes

    • Received December 7, 2015.
    • Accepted January 20, 2016.
  • Dr. Rondini was funded, in part, through a postdoctoral fellowship awarded through the Office of Vice President of Research (Wayne State University, Detroit, MI). This research was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01 HL050710] and the National Institute of Environmental Health Sciences [Center Grant P30 ES020957].

  • dx.doi.org/10.1124/dmd.115.068551.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

Nonsterol Isoprenoids Activate hCAR1

Elizabeth A. Rondini, Zofia Duniec-Dmuchowski and Thomas A. Kocarek
Drug Metabolism and Disposition April 1, 2016, 44 (4) 595-604; DOI: https://doi.org/10.1124/dmd.115.068551

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Research ArticleArticle

Nonsterol Isoprenoids Activate hCAR1

Elizabeth A. Rondini, Zofia Duniec-Dmuchowski and Thomas A. Kocarek
Drug Metabolism and Disposition April 1, 2016, 44 (4) 595-604; DOI: https://doi.org/10.1124/dmd.115.068551
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