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

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Elizabeth A RondiniThomas A Kocarek

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 i...Continue Reading

References

Dec 1, 1994·Archives of Biochemistry and Biophysics·V S Bansal, S Vaidya
Apr 19, 1996·The Journal of Biological Chemistry·P HonkakoskiM Negishi
Apr 4, 1997·The Journal of Biological Chemistry·R G BostedorJ D Bergstrom
Feb 25, 1998·Biochemical and Biophysical Research Communications·S S Krag
Feb 26, 1999·The Journal of Biological Chemistry·T SueyoshiM Negishi
Jun 29, 2000·Annual Review of Biochemistry·P A Edwards, J Ericsson
Oct 18, 2000·Free Radical Biology & Medicine·G Dallner, P J Sindelar
Aug 4, 2001·Biochemical and Biophysical Research Communications·Y SakakuraK Inoue
Mar 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Wendong HuangDavid D Moore
Jun 12, 2003·Nucleic Acids Research·Scott S AuerbachCurtis J Omiecinski
Oct 22, 2003·Molecular Genetics and Metabolism·Rajesh S SavkurThomas P Burris
Mar 9, 2004·The Journal of Biological Chemistry·Jodi M MaglichJohn T Moore
Jun 15, 2004·The Journal of Pharmacology and Experimental Therapeutics·Jatinder K LambaErin Schuetz
Oct 17, 2006·The Journal of Pharmacology and Experimental Therapeutics·Stephanie R FaucetteHongbing Wang
Nov 14, 2006·Nature Methods·Ingrid Remy, Stephen W Michnick
Dec 30, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Scott S AuerbachCurtis J Omiecinski
Mar 22, 2007·BioTechniques·Ingrid Remy, Stephen W Michnick
Aug 2, 2007·Molecular Endocrinology·Sharmistha DasHerbert H Samuels
Jul 12, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nancy M Jackson, Thomas A Kocarek
Jul 15, 2009·Trends in Endocrinology and Metabolism : TEM·Taira WadaWen Xie
Oct 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Bingning DongDavid D Moore

❮ Previous
Next ❯

Citations

Nov 5, 2020·Cells·Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin
Jun 1, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Anna MukhaSaskia W C van Mil
May 21, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Liberta CukoThomas A Kocarek

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alternative splicing

Alternative splicing a regulated gene expression process that allows a single genetic sequence to code for multiple proteins. Here is that latest research.