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Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids

  • Original article
  • Published:
Journal of Hepato-Biliary-Pancreatic Sciences

Abstract

Background/Purpose

Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis.

Methods

Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined.

Results

The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na+-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression.

Conclusions

The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.

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Abbreviations

ABC:

ATP binding cassette

BSEP:

Bile acid export pump to bile duct

DHE:

Dihydroethidium

CAR:

Constitutive androstane receptor

FXR:

Farnesoid X receptor

GCDCA:

Glycochenodeoxycholic acid

GR:

Glucocorticoid receptor

LDH:

Lactate dehydrogenase

MTP:

Mitochondrial transmembrane potential

MRP:

Multidrug resistance-associated protein

NTCP:

Na+-taurocholate co-transporting polypeptide

OATP:

Organic anion transporting polypeptide

PXR:

Pregnane X receptor

ROS:

Reactive oxygen species

UGT2B4:

UDP-glucuronosyltransferase 2B4

VDR:

Vitamin D receptor

References

  1. Starzl TE, Demetris AJ, Van TD. Liver transplantation (1). N Engl J Med. 1989;321:1014–22.

    Article  PubMed  CAS  Google Scholar 

  2. Hofmann AF. Chemistry and enterohepatic circulation of bile acids. Hepatology. 1984;4:4S–14S.

    Article  PubMed  CAS  Google Scholar 

  3. Galle PR, Theilmann L, Raedsch R, et al. Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology. 1990;12:486–91.

    Article  PubMed  CAS  Google Scholar 

  4. Patel T, Bronk SF, Gores GJ. Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes. J Clin Invest. 1994;94:2183–92.

    Article  PubMed  CAS  Google Scholar 

  5. Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med. 2005;171:699–706.

    Article  PubMed  Google Scholar 

  6. Gillespie DA, Vickers CR. Pruritus and cholestasis: therapeutic options. J Gastroenterol Hepatol. 1993;8:168–73.

    Article  PubMed  CAS  Google Scholar 

  7. Berg CL, Gollan JL. Primary biliary cirrhosis: new therapeutic directions. Scand J Gastroenterol Suppl. 1992;192:43–9.

    Article  PubMed  CAS  Google Scholar 

  8. Cancado EL, Leitao RM, Carrilho FJ. Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase. Am J Gastroenterol. 1998;93:1510–7.

    PubMed  CAS  Google Scholar 

  9. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest. 1991;99:465–71.

    Article  PubMed  CAS  Google Scholar 

  10. Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut. 2002;50:436–9.

    Article  PubMed  CAS  Google Scholar 

  11. Meyer UA. Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm. 1996;24:449–59.

    Article  PubMed  CAS  Google Scholar 

  12. Schoene B, Fleischmann RA, Remmer H, et al. Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J Clin Pharmacol. 1972;4:65–73.

    Article  PubMed  CAS  Google Scholar 

  13. Hoensch HP, Balzer K, Dylewizc P, Kirch W, Goebell H, Ohnhaus EE. Effect of rifampicin treatment on hepatic drug metabolism and serum bile acids in patients with primary biliary cirrhosis. Eur J Clin Pharmacol. 1985;28:475–7.

    Article  PubMed  CAS  Google Scholar 

  14. Chen J, Raymond K. Roles of rifampicin in drug–drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob. 2006;5:3.

    Article  PubMed  Google Scholar 

  15. Muntane J. Regulation of drug metabolism and transporters. Curr Drug Metab. 2009;10:932–45.

    Article  PubMed  CAS  Google Scholar 

  16. Lim YP, Huang JD. Interplay of pregnane X receptor with other nuclear receptors on gene regulation. Drug Metab Pharmacokinet. 2008;23:14–21.

    Article  PubMed  CAS  Google Scholar 

  17. Pascussi JM, Gerbal-Chaloin S, Drocourt L, et al. The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta. 2003;1619:243–53.

    PubMed  CAS  Google Scholar 

  18. Rae JM, Johnson MD, Lippman ME, et al. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther. 2001;299:849–57.

    PubMed  CAS  Google Scholar 

  19. Soars MG, Petullo DM, Eckstein JA, et al. An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes. Drug Metab Dispos. 2004;32:140–8.

    Article  PubMed  CAS  Google Scholar 

  20. Dilger K, Greiner B, Fromm MF, et al. Consequences of rifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2D6. Pharmacogenetics. 1999;9:551–9.

    Article  PubMed  CAS  Google Scholar 

  21. Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001;276:14581–7.

    Article  PubMed  CAS  Google Scholar 

  22. Frank C, Makkonen H, Dunlop TW, et al. Identification of pregnane X receptor binding sites in the regulatory regions of genes involved in bile acid homeostasis. J Mol Biol. 2005;346:505–19.

    Article  PubMed  CAS  Google Scholar 

  23. Hirano M, Maeda K, Shitara Y, et al. Drug–drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos. 2006;34:1229–36.

    Article  PubMed  CAS  Google Scholar 

  24. Ehret MJ, Levin GM, Narasimhan M, et al. Venlafaxine induces P-glycoprotein in human Caco-2 cells. Hum Psychopharmacol. 2007;22:49–53.

    Article  PubMed  CAS  Google Scholar 

  25. Monte MJ, Marin JJ, Antelo A, et al. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol. 2009;15:804–16.

    Article  PubMed  CAS  Google Scholar 

  26. Pichard L, Raulet E, Fabre G, et al. Human hepatocyte culture. Methods Mol Biol. 2006;320:283–93.

    PubMed  Google Scholar 

  27. Gonzalez R, Collado JA, Nell S, et al. Cytoprotective properties of alpha-tocopherol are related to gene regulation in cultured d-galactosamine-treated human hepatocytes. Free Radic Biol Med. 2007;43:1439–52.

    Article  PubMed  CAS  Google Scholar 

  28. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15:1677–89.

    Article  PubMed  CAS  Google Scholar 

  29. Yerushalmi B, Dahl R, Devereaux MW, et al. Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology. 2001;33:616–26.

    Article  PubMed  CAS  Google Scholar 

  30. Sokol RJ, McKim JM Jr, Goff MC, et al. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology. 1998;114:164–74.

    Article  PubMed  CAS  Google Scholar 

  31. Soden JS, Devereaux MW, Haas JE, et al. Subcutaneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasis. Hepatology. 2007;46:485–95.

    Article  PubMed  CAS  Google Scholar 

  32. Menke JG, Macnaul KL, Hayes NS, et al. A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a). Endocrinology. 2002;143:2548–58.

    Article  PubMed  CAS  Google Scholar 

  33. Martinez-Jimenez CP, Jover R, Donato MT, et al. Transcriptional regulation and expression of CYP3A4 in hepatocytes. Curr Drug Metab. 2007;8:185–94.

    Article  PubMed  CAS  Google Scholar 

  34. Marschall HU, Wagner M, Zollner G, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 2005;129:476–85.

    PubMed  Google Scholar 

  35. Hinson JA, Forkert PG. Phase II enzymes and bioactivation. Can J Physiol Pharmacol. 1995;73:1407–13.

    Article  PubMed  CAS  Google Scholar 

  36. Jung D, Mangelsdorf DJ, Meyer UA. Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem. 2006;281:19081–91.

    Article  PubMed  CAS  Google Scholar 

  37. Zhang J, Huang W, Qatanani M, et al. The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. J Biol Chem. 2004;279:49517–22.

    Article  PubMed  CAS  Google Scholar 

  38. Zollner G, Fickert P, Zenz R, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology. 2001;33:633–46.

    Article  PubMed  CAS  Google Scholar 

  39. Shoda J, Kano M, Oda K, et al. The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliaty secretory function. Am J Gastroenterol. 2001;96:3368–78.

    Article  PubMed  CAS  Google Scholar 

  40. Oswald M, Kullak-Ublick GA, Paumgartner G, et al. Expression of hepatic transporters OATP-C and MRP2 in primary sclerosing cholangitis. Liver. 2001;21:247–53.

    Article  PubMed  CAS  Google Scholar 

  41. Zollner G, Fickert P, Silbert D, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003;38:717–27.

    Article  PubMed  CAS  Google Scholar 

  42. Elferink MG, Olinga P, Draaisma AL, et al. LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttrancriptional process. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1008–16.

    Article  PubMed  CAS  Google Scholar 

  43. Geier A, Zollner G, Dietrich CG, et al. Cytokine-independent repression of rodent Ntcp in obstructive cholestasis. Hepatology. 2005;41:470–7.

    Article  PubMed  CAS  Google Scholar 

  44. Watanabe N, Takashimizu S, Kojima S, et al. Clinical and pathological features of a prolonged type of acute intrahepatic cholestasis. Hepatol Res. 2007;37:598–607.

    Article  PubMed  CAS  Google Scholar 

  45. Ananthanarayanan M, Balasubramanian N, Makishima M, et al. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001;276:28857–65.

    Article  PubMed  CAS  Google Scholar 

  46. Kast HR, Goodwin B, Tarr PT, et al. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem. 2002;277:2908–15.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study has been supported by the Instituto de Salud Carlos III (FIS 02/0181, FIS 05/0703 and FIS 07/0159) and Consejería de Salud (SAS 50/03 and SAS 99/06). CIBERehd was funded by the Instituto de Salud Carlos III.

Author information

Authors and Affiliations

  1. Liver Research Unit, Hospital Universitario Reina Sofía, IMIBIC (Instituto Maimónides para la Investigación Biomédica de Córdoba), Av. Menéndez Pidal s/n, 14004, Córdoba, Spain

    Raúl González, Gustavo Ferrín & Jordi Muntané

  2. Department of General Surgery, “Valle de los Pedroches” General Hospital, Pozoblanco, Córdoba, Spain

    Adolfo Cruz

  3. Surgery Department, IMIBIC (Instituto Maimónides para la Investigación Biomédica de Córdoba), “Reina Sofia” University Hospital, Córdoba, Spain

    Pedro López-Cillero, Javier Briceño & Sebastián Rufián

  4. Department of General Surgery, “Virgen del Rocío”, University Hospital (IBiS), Seville, Spain

    Miguel A. Gómez & Javier Padillo

  5. Gastroenterology Department, IMIBIC (Instituto Maimónides para la Investigación Biomédica de Córdoba), “Reina Sofia” University Hospital, Córdoba, Spain

    Manuel De la Mata

  6. Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain

    Jose J. G. Marin

  7. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

    Raúl González, Adolfo Cruz, Gustavo Ferrín, Pedro López-Cillero, Javier Briceño, Sebastián Rufián, Javier Padillo, Manuel De la Mata, Jose J. G. Marin & Jordi Muntané

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  1. Raúl González
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  11. Jordi Muntané
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Correspondence to Jordi Muntané.

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González, R., Cruz, A., Ferrín, G. et al. Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids. J Hepatobiliary Pancreat Sci 18, 740–750 (2011). https://doi.org/10.1007/s00534-011-0396-3

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  • DOI: https://doi.org/10.1007/s00534-011-0396-3

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