Cardiovascular Toxicology

, Volume 5, Issue 1, pp 63–73 | Cite as

Bile acids are toxic for isolated cardiac mitochondria

A possible cause for Hepatic-derived cardiomyopathies?
  • Manuela Ferreira
  • Pedro M. Coxito
  • Vilma A. Sardão
  • Carlos M. Palmeira
  • Paulo J. Oliveira
Article

Abstract

Cholestasis and other liver diseases may affect the heart through the toxic effects of the retained bile acids on cardiac mitochondria, which could explain the origin of hepatic-derived cardiomyopathies.

The objective of this work was to test the hypothesis that bile acids are toxic to heart mitochondria for concentrations that are relevant for cholestasis.

Heart mitochondria were isolated from rat and subjected to incubation with selected bile acids (litocholic acid [LCA], deoxycholic acid [DCA], chenodeoxycholic acid [CDCA], glycochenodeoxycholic acid [GCDC], taurodeoxycholic acid [CDCA], and glycoursodeoxycholic acid [GUDC]).

We observed that the most toxic bile acids were also the most lipophilic ones (LCA, DCA, and CDCA), inducing a decrease on state 3 respiration, respiratory control ratio, and membrane potential and causing the induction of the mitochondrial permeability transition. GUDC was the bile acid with lower indexes of toxicity on isolated heart mitochondria.

The results of this research indicate that attoxicologically relevant concentrations, most bile acids (mainly the most lipophilic) alter mitochondrial bioenergetics. The impairment of cardiac mitochondrial function may be an important cause for the observed cardiac alterations during cholestasis.

Key Words

Cardiac mitochondria mitochondrial permeability transition hepatic disease cholestasis bile acids 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Greim, H., Trulzch, D., Czygan, P., Rudick, J. Hutterer, F., Schaffner, F., and Popper, H. (1972). Mechanisms of cholestasis. 6. Bile salts in human livers with or without biliary obstruction. Gastroenterology 63:846–850.PubMedGoogle Scholar
  2. 2.
    Shivaram, K.N., Winklhofer-Roob, B.M., Straka, M.S., Devereaux, M.W., Everson, G., Mierau, G.W., and Sokol, R.J. (1998). The effect of idebenone, a coenzyme analogue, on hydrophobic bile acid toxicity to isolated rat hepatocytes and hepatic mitochondria. Free Rad. Biol. Med. 25: 480–492.PubMedCrossRefGoogle Scholar
  3. 3.
    Sokol, R.J., McKim, J.M., Goff, M.C., Ruyle, S.Z., Devereaux, M.W., Han, D., et al. (1998). Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochemodeoxycholic acid in the rat. Gastroenterology 114:164–174.PubMedCrossRefGoogle Scholar
  4. 4.
    Rodrigues, C.M.P. and Steer, C.J. (2000). Mitochondrial membrane perturbations in cholestasis. J. Hepatol. 32: 135–141.PubMedCrossRefGoogle Scholar
  5. 5.
    Krahenbuhl, S., Talos, C., Fischer, S., and Reichen, J. (1994). Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 19:471–479.PubMedGoogle Scholar
  6. 6.
    Guldutuna, S., Zimmer, G., Leuschner, M., Bhatti, S., Elze, A., Deisinger, B., et al. (1999). The effect of bile salts and calcium on isolated rat liver mitochondria. Biochim. Biophys. Acta 1453:396–406.PubMedGoogle Scholar
  7. 7.
    Rolo, A.P., Oliveira, P.J., Moreno, A.J.M., and Palmeira, C.M. (2000). Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy. Toxicol. Sci. 57:177–185.PubMedCrossRefGoogle Scholar
  8. 8.
    Zoratti, M. and Szabò, I. (1995). The mitochondrial permeability transition. Biochim. Biophys. Acta 1241:139–176.PubMedGoogle Scholar
  9. 9.
    Kowaltowski, A.J., Castilho, R.F., and Vercesi, A.E. (2201). Mitochondrial permeability transition and oxidative stress. FEBS Lett. 495:12–15.CrossRefGoogle Scholar
  10. 10.
    Kroemer, G. and Reed, J.C. (2000). Mitochondrial control of cell death. Nature Med. 6:513–519.PubMedCrossRefGoogle Scholar
  11. 11.
    Gores, G.J., Miyoshi, H., Botla, R., Aguilar, H.I., and Bronk, S.F. (1998). Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: a potential role for mitochondrial proteases. Biochim. Biophys. Acta 1366:167–175.PubMedCrossRefGoogle Scholar
  12. 12.
    Yerushalmi, B., Dahl, R., Devereaux, M.W., Gumpricht, E., and Sokol, R.J. (2001). Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology 33: 616–626.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee, S.S. and Bomzon, A. (1990). The heart in liver disease, in: Cardiovascular Complications of Liver Disease (Bomzon, A. and Blendis, L.M., eds.) CRC, Boca Raton, FL: pp. 81–102.Google Scholar
  14. 14.
    Moller, S. and Henriksen, J.H. (2002). Cirrhotic cardiomyopathy: a pathophysiological review of circulatory dysfunction in liver disease. Heart 87:9–15.PubMedCrossRefGoogle Scholar
  15. 15.
    Gazawi, H., Ljubuncic, P., Cogan, U., Hochgraff, E., Ben-Shachar, D., and Bomzon, A. (2000). The effects of bile acids on β-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes. Biochem. Pharmacol. 59:1623–1628.PubMedCrossRefGoogle Scholar
  16. 16.
    Williamson, C., Gorelik, J., Eaton, B.M., Lab, M., de Swiet, M., and Korchev, Y. (2001). The bile acid taaurocholate impairs rat cardiomyocyte function: a proposed mechanism for intra-uterine fetal death in obstetric cholestasis. Clin. Sci. 100:363–369.PubMedCrossRefGoogle Scholar
  17. 17.
    Rolo, A.P., Oliveira, P.J., Seiça, R., Santos, M.S., Moreno, A.J., and Palmeira, C.M. (2002). Improved efficiency of hepatic mitochondrial function in rats with cholestasis induced by an acute dose of alfa-naphtylisothiocyanate. Toxicol. Appl. Pharmacol. 182:20–26.PubMedCrossRefGoogle Scholar
  18. 18.
    Rolo, A.P., Oliveira, P.J., Seiça, R., Santos, M.S., Moreno, A.J., and Palmeira, C.M. (2002). Disruption of mitochondrial calcium homeostasis after chronic α-naphthylisothiocyanate administration: relevance for cholestasis. J. Investig. Med. 50:193–200.PubMedGoogle Scholar
  19. 19.
    Oliveira, P.J., Rolo, A.P., Seiça, R., Santos, M.S., Palmeira, C.M., and Moreno, A.J. (2003a). Reduction in cardiac mitochondrial calcium loading capacity is observable during α-naphylisothiocyanate-induced acute cholestasis: a clue for hepatic-derived cardiomyopathies? Biochim. Biophys. Acta 1637:39–45.PubMedGoogle Scholar
  20. 20.
    Oliveira, P.J., Rolo, A.P., Seica, R., Santos, M.S., Palmeira, C.M., and Moreno, A.J. (2003b). Cardiac mitochondrial calcium loading capacity is severely affected after chronic cholestasis in Wistar rats. J. Invest. Med. 51:86–94.Google Scholar
  21. 21.
    Fischer, S., Beuers, U., Spengler, U., Zwiebel, F.M., and Koebe, H.-G. (1996). Hepatic levels of bile acids in endstage chronic cholestatic liver disease. Clin. Chim. Acta 251:173–186.PubMedCrossRefGoogle Scholar
  22. 22.
    (No authors listed) (1996). Principles of Laboratory Animal Care. NIH publication No. 85-23. National Institutes of Health, Bethesda, MD.Google Scholar
  23. 23.
    Oliveira, P.J., Santos, D.L., and Moreno, A.J.M. (2000). Carvedilol inhibits the exogenous NADH dehydrogenase in rat heart mitochondria. Arch. Biochem. Biophys. 374: 279–285.PubMedCrossRefGoogle Scholar
  24. 24.
    Kamo, N., Muratsugu, M., Hongoh, R., and Kobatake, Y. (1979). Membrane potential of mitochondria measured with an electrode sensitive to tetraphenyl phosphonium and relationship between proton electrochemical potential and phosphorylation potential in steady state. J. Membrane Biol. 49:105–121.CrossRefGoogle Scholar
  25. 25.
    Broekemeier, K.M., Dempsey, M.E., and Pfeiffer, D.R. (1989). Cyclosporin A is a potent inhibitor of the inner membrane mitochondrial transition in liver mitochondria. J. Biol. Chem. 264:7826–7830.PubMedGoogle Scholar
  26. 26.
    Makino, I., Nakagawa, S., and Mashimo, K. (1969). Conjugated and unconjugated serum bile acid levels in patients with hepatobiliary diseases Gastroenterology 56:1033–1039.PubMedGoogle Scholar
  27. 27.
    Ostrow, J.D. (1993). Metabolism of bile salts in cholestasis in humans, in Hepatic Transport and Bile Secretion: Physiology and Pathophysiology (Tavoloni, N. and Berk, P.D., eds.), Raven, New York: pp. 673–712.Google Scholar
  28. 28.
    Bartholomew, T.C., Summerfield, J.A., Billing, B.H., and Lawson, A.M. (1982). Bile acid profiles of human serum and skin interstitial fluid and their relationship to pruritus studied by gas chromatography-mass spectrometry. Clin. Sci. 63:65–73.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Manuela Ferreira
    • 1
  • Pedro M. Coxito
    • 1
  • Vilma A. Sardão
    • 1
  • Carlos M. Palmeira
    • 1
  • Paulo J. Oliveira
    • 1
  1. 1.Centro de Neurociências e Biologia Celular de Coimbra, Dept. Zoologia, Faculdade de Ciências e TecnologiaUniversidade de CoimbraCoimbraPortugal

Personalised recommendations