The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Brandy GarzelHongbing Wang

Abstract

The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of BSEP transcription would contribute to drug-induced cholestasis is largely unknown. In this study, we selected 30 drugs previously reported as BSEP inhibitors to evaluate their effects on BSEP expression, farnesoid X receptor (FXR) activation, and correlations to clinically reported liver toxicity. Our results indicate that of the 30 BSEP inhibitors, five exhibited potent repression of BSEP expression (≥60% repression), ten were moderate repressors (20-60% repression), whereas others had negligible effects (≤20% repression). Of importance, two drugs (troglitazone and benzbromarone), previously withdrawn from the market because of liver injury, are among the potent repressors. Further investigation of the five potent repressors revealed tha...Continue Reading

References

Sep 1, 1976·The American Journal of Physiology·J Reichen, G Paumgartner
Jul 6, 1995·Biochimica Et Biophysica Acta·N L SimmonsM A Jepson
May 21, 1999·Science·M MakishimaB Shan
Jun 2, 2001·The Journal of Biological Chemistry·M AnanthanarayananF J Suchy
Jun 28, 2001·Physiological Reviews·A Aranda, A Pascual
Aug 29, 2003·Toxicological Sciences : an Official Journal of the Society of Toxicology·Vsevolod E KostrubskyJasminder Sahi
Mar 11, 2005·Journal of Clinical Gastroenterology·Willis C Maddrey
May 12, 2005·Biochemical Pharmacology·C GardmoA Mode
Jul 19, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Einar Björnsson, Rolf Olsson
Mar 4, 2006·The Journal of Pharmacology and Experimental Therapeutics·Stephanie R FaucetteHongbing Wang
Feb 14, 2008·Journal of Lipid Research·Xiulong SongRuitang Deng
Oct 7, 2008·World Journal of Gastroenterology : WJG·Alejandro Esteller
Apr 17, 2009·The Journal of Pharmacology and Experimental Therapeutics·Rajani KaimalRuitang Deng
Aug 18, 2009·Current Opinion in Lipidology·Bruno Stieger
Oct 13, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jittima WeerachayaphornJames L Boyer
Sep 11, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ryan E MorganHisham K Hamadeh
Jun 1, 2011·Drug Discovery Today·Minjun ChenWeida Tong
Oct 4, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sarah DawsonJ Gerald Kenna
Nov 24, 2011·Biochemical and Biophysical Research Communications·Eiichiro OgimuraToshiharu Horie
Jul 17, 2012·Clinics and Research in Hepatology and Gastroenterology·Ralf KubitzDieter Häussinger
Nov 22, 2012·Current Protocols in Toxicology·Carlo J van StadenHisham K Hamadeh
Jan 31, 2013·Toxicology and Applied Pharmacology·Makoto YamazakiLining Guo

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Citations

Jul 10, 2014·CPT: Pharmacometrics & Systems Pharmacology·J L WoodheadB A Howell
Jun 28, 2016·Archives of Toxicology·Suresh VatakutiGeny M M Groothuis
Jul 8, 2016·Journal of Clinical Pharmacology·Houfu Liu, Jasminder Sahi
Oct 19, 2016·Journal of Digestive Diseases·Zhi Qing Yuan, Ke Wei Li
Oct 21, 2016·Scientific Reports·Delilah F G HendriksMagnus Ingelman-Sundberg
Aug 20, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Matthew G BurbankAndré Guillouzo
Apr 8, 2017·Journal of Pharmaceutical Sciences·Bruno Stieger, Zainab M Mahdi
May 16, 2018·Archives of Toxicology·Robim M RodriguesMathieu Vinken
Apr 4, 2017·Toxicological Sciences : an Official Journal of the Society of Toxicology·Matthew Gibson BurbankAndré Guillouzo
Jul 18, 2018·International Journal of Molecular Sciences·Chang Yeob Han
May 2, 2020·Journal of Medical Toxicology : Official Journal of the American College of Medical Toxicology·Michael A CharyMichele M Burns
Oct 8, 2019·Critical Reviews in Toxicology·Neel DefermPieter Annaert
Oct 22, 2016·Archives of Toxicology·Christoph Funk, Adrian Roth
Jan 8, 2020·Pharmaceutical Research·Brandy GarzelHongbing Wang
Apr 12, 2019·Archives of Toxicology·Eva GijbelsMathieu Vinken
Dec 15, 2020·Chemical Research in Toxicology·James W FirmanMark T D Cronin
Jan 21, 2021·International Journal of Molecular Sciences·Muhammad Imran SohailPeter Chiba
Dec 17, 2020·Journal of the Chinese Medical Association : JCMA·Yi-Shin HuangYi-Hsiang Huang
Jun 5, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Thomas KraljDarren J Creek
Aug 14, 2021·Journal of Evidence-based Medicine·Jing-Quan WangZhe-Sheng Chen

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