Download PDF
Semin Liver Dis 2010; 30(2): 195-204
DOI: 10.1055/s-0030-1253228
© Thieme Medical Publishers

Oxidative Stress and the Pathogenesis of Cholestasis

Bryan L. Copple1 , Hartmut Jaeschke1 , Curtis D. Klaassen1
  • 1Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
Further Information

Publication History

Publication Date:
26 April 2010 (online)

    Permissions and Reprints

ABSTRACT

Cholestasis is a reduction in bile flow that occurs from a variety of causes in humans. This produces hepatocellular injury and fibrosis. Considering that there are limited therapies for this disease, there has been interest in understanding the mechanism by which cholestasis produces injury. Studies have demonstrated that oxidative stress occurs in livers of humans with cholestasis. In vitro studies have demonstrated that bile acids kill hepatocytes by a mechanism that depends upon reactive oxygen species (ROS). Further studies, however, have demonstrated that this mechanism is of limited importance in vivo. Cholestasis also initiates an inflammatory response resulting in accumulation of neutrophils in the liver. Inhibition of neutrophil function reduces oxidative stress and liver injury suggesting that neutrophils are an important source of damaging ROS in vivo. Furthermore, inhibition of ROS during cholestasis reduces fibrosis. Collectively, these studies suggest that ROS are important for pathologic changes that occur during cholestasis.

KEYWORDS

Oxidative stress - hepatocytes - inflammation - fibrosis - bile acids - cholestasis

REFERENCES

  • 1 Qureshi W A. Intrahepatic cholestatic syndromes: pathogenesis, clinical features and management.  Dig Dis. 1999;  17(1) 49-59
    CrossrefPubMedGoogle Scholar
  • 2 Kim W R, Ludwig J, Lindor K D. Variant forms of cholestatic diseases involving small bile ducts in adults.  Am J Gastroenterol. 2000;  95(5) 1130-1138
    CrossrefPubMedGoogle Scholar
  • 3 Poupon R, Chazouillères O, Poupon R E. Chronic cholestatic diseases.  J Hepatol. 2000;  32(1, Suppl) 129-140
    PubMedGoogle Scholar
  • 4 Murphy M P. How mitochondria produce reactive oxygen species.  Biochem J. 2009;  417(1) 1-13
    CrossrefPubMedGoogle Scholar
  • 5 Schrader M, Fahimi H D. Peroxisomes and oxidative stress.  Biochim Biophys Acta. 2006;  1763(12) 1755-1766
    CrossrefPubMedGoogle Scholar
  • 6 Bedard K, Krause K H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.  Physiol Rev. 2007;  87(1) 245-313
    CrossrefPubMedGoogle Scholar
  • 7 Jaeschke H. Cellular antioxidant defense mechanisms. In: Roth RA, Ganey P Comprehensive Toxicology, Volume IX: Hepatic Toxicology. Oxford, UK; Elsevier 2010 In press
    Google Scholar
  • 8 Jaeschke H, Knight T R, Bajt M L. The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity.  Toxicol Lett. 2003;  144(3) 279-288
    CrossrefPubMedGoogle Scholar
  • 9 Li Y, Huang T T, Carlson E J et al.. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase.  Nat Genet. 1995;  11(4) 376-381
    CrossrefPubMedGoogle Scholar
  • 10 Mathews W R, Guido D M, Fisher M A, Jaeschke H. Lipid peroxidation as molecular mechanism of liver cell injury during reperfusion after ischemia.  Free Radic Biol Med. 1994;  16(6) 763-770
    CrossrefPubMedGoogle Scholar
  • 11 Hong J Y, Lebofsky M, Farhood A, Jaeschke H. Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation.  Am J Physiol Gastrointest Liver Physiol. 2009;  296(3) G572-G581
    CrossrefPubMedGoogle Scholar
  • 12 Nieminen A L, Saylor A K, Tesfai S A, Herman B, Lemasters J J. Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide.  Biochem J. 1995;  307(Pt 1) 99-106
    PubMedGoogle Scholar
  • 13 Sokol R J, Devereaux M, Khandwala R A. Effect of dietary lipid and vitamin E on mitochondrial lipid peroxidation and hepatic injury in the bile duct-ligated rat.  J Lipid Res. 1991;  32(8) 1349-1357
    PubMedGoogle Scholar
  • 14 Parola M, Leonarduzzi G, Robino G, Albano E, Poli G, Dianzani M U. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis.  Free Radic Biol Med. 1996;  20(3) 351-359
    CrossrefPubMedGoogle Scholar
  • 15 Singh S, Shackleton G, Ah-Sing E, Chakraborty J, Bailey M E. Antioxidant defenses in the bile duct-ligated rat.  Gastroenterology. 1992;  103(5) 1625-1629
    PubMedGoogle Scholar
  • 16 Pastor A, Collado P S, Almar M, González-Gallego J. Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine.  J Hepatol. 1997;  27(2) 363-370
    CrossrefPubMedGoogle Scholar
  • 17 Lemonnier F, Cresteil D, Fénéant M, Couturier M, Bernard O, Alagille D. Plasma lipid peroxides in cholestatic children.  Acta Paediatr Scand. 1987;  76(6) 928-934
    CrossrefPubMedGoogle Scholar
  • 18 Tazawa Y, Nakagawa M, Yamada M et al.. Serum vitamin E levels in children with corrected biliary atresia.  Am J Clin Nutr. 1984;  40(2) 246-250
    PubMedGoogle Scholar
  • 19 Weinberger B, Watorek K, Strauss R, Witz G, Hiatt M, Hegyi T. Association of lipid peroxidation with hepatocellular injury in preterm infants.  Crit Care. 2002;  6(6) 521-525
    CrossrefPubMedGoogle Scholar
  • 20 Belli D C, Fournier L A, Lepage G et al.. Total parenteral nutrition-associated cholestasis in rats: comparison of different amino acid mixtures.  JPEN J Parenter Enteral Nutr. 1987;  11(1) 67-73
    CrossrefPubMedGoogle Scholar
  • 21 Kitada T, Seki S, Iwai S, Yamada T, Sakaguchi H, Wakasa K. In situ detection of oxidative DNA damage, 8-hydroxydeoxyguanosine, in chronic human liver disease.  J Hepatol. 2001;  35(5) 613-618
    CrossrefPubMedGoogle Scholar
  • 22 Aboutwerat A, Pemberton P W, Smith A et al.. Oxidant stress is a significant feature of primary biliary cirrhosis.  Biochim Biophys Acta. 2003;  1637(2) 142-150
    PubMedGoogle Scholar
  • 23 Vendemiale G, Grattagliano I, Lupo L, Memeo V, Altomare E. Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage.  J Hepatol. 2002;  37(5) 601-605
    CrossrefPubMedGoogle Scholar
  • 24 Klaassen C D, Reisman S A. Nrf2 the Rescue: Effects of the antioxidative/electrophilic response on the liver.  Toxicol Appl Pharmacol. 2010;  244(1) 57-65
    CrossrefPubMedGoogle Scholar
  • 25 Maher J M, Cheng X, Slitt A L, Dieter M Z, Klaassen C D. Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver.  Drug Metab Dispos. 2005;  33(7) 956-962
    CrossrefPubMedGoogle Scholar
  • 26 Maher J M, Dieter M Z, Aleksunes L M et al.. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway.  Hepatology. 2007;  46(5) 1597-1610
    CrossrefPubMedGoogle Scholar
  • 27 Reisman S A, Csanaky I L, Aleksunes L M, Klaassen C D. Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice.  Toxicol Sci. 2009;  109(1) 31-40
    CrossrefPubMedGoogle Scholar
  • 28 Cheng X, Buckley D, Klaassen C D. Regulation of hepatic bile acid transporters Ntcp and Bsep expression.  Biochem Pharmacol. 2007;  74(11) 1665-1676
    CrossrefPubMedGoogle Scholar
  • 29 Weerachayaphorn J, Cai S Y, Soroka C J, Boyer J L. Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression.  Hepatology. 2009;  50(5) 1588-1596
    CrossrefPubMedGoogle Scholar
  • 30 Sokol R J, Devereaux M, Khandwala R, O'Brien K. Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes.  Hepatology. 1993;  17(5) 869-881
    CrossrefPubMedGoogle Scholar
  • 31 Sokol R J, Winklhofer-Roob B M, Devereaux M W, McKim Jr J M. Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids.  Gastroenterology. 1995;  109(4) 1249-1256
    CrossrefPubMedGoogle Scholar
  • 32 Fang Y, Han S I, Mitchell C et al.. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes.  Hepatology. 2004;  40(4) 961-971
    PubMedGoogle Scholar
  • 33 Graf D, Kurz A K, Fischer R, Reinehr R, Häussinger D. Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner.  Gastroenterology. 2002;  122(5) 1411-1427
    CrossrefPubMedGoogle Scholar
  • 34 Patel T, Bronk S F, Gores G J. Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes.  J Clin Invest. 1994;  94(6) 2183-2192
    CrossrefPubMedGoogle Scholar
  • 35 Miyoshi H, Rust C, Roberts P J, Burgart L J, Gores G J. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas.  Gastroenterology. 1999;  117(3) 669-677
    CrossrefPubMedGoogle Scholar
  • 36 Fickert P, Trauner M, Fuchsbichler A et al.. Oncosis represents the main type of cell death in mouse models of cholestasis.  J Hepatol. 2005;  42(3) 378-385
    CrossrefPubMedGoogle Scholar
  • 37 Gujral J S, Liu J, Farhood A, Jaeschke H. Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation.  Hepatology. 2004;  40(4) 998-1007
    PubMedGoogle Scholar
  • 38 Schoemaker M H, Gommans W M, Conde de la Rosa L et al.. Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation.  J Hepatol. 2003;  39(2) 153-161
    CrossrefPubMedGoogle Scholar
  • 39 Nalapareddy P, Schüngel S, Hong J Y, Manns M P, Jaeschke H, Vogel A. The BH3-only protein bid does not mediate death-receptor-induced liver injury in obstructive cholestasis.  Am J Pathol. 2009;  175(3) 1077-1085
    CrossrefPubMedGoogle Scholar
  • 40 Reinehr R, Graf D, Häussinger D. Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation.  Gastroenterology. 2003;  125(3) 839-853
    CrossrefPubMedGoogle Scholar
  • 41 Allen K, Kim N D, Copple B L. Bile acids increase proinflammatory gene expression in hepatocytes by early growth response factor-1-dependent and independent mechanisms (abstract).  Toxicol Sci. 2010;  114(Suppl. 1) 344
    PubMedGoogle Scholar
  • 42 Saito J M, Maher J J. Bile duct ligation in rats induces biliary expression of cytokine-induced neutrophil chemoattractant.  Gastroenterology. 2000;  118(6) 1157-1168
    CrossrefPubMedGoogle Scholar
  • 43 Gujral J S, Farhood A, Bajt M L, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice.  Hepatology. 2003;  38(2) 355-363
    PubMedGoogle Scholar
  • 44 Gujral J S, Liu J, Farhood A, Hinson J A, Jaeschke H. Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice.  Am J Physiol Gastrointest Liver Physiol. 2004;  286(3) G499-G507
    CrossrefPubMedGoogle Scholar
  • 45 Georgiev P, Jochum W, Heinrich S et al.. Characterization of time-related changes after experimental bile duct ligation.  Br J Surg. 2008;  95(5) 646-656
    CrossrefPubMedGoogle Scholar
  • 46 Kennedy J A, Lewis H, Clements W D et al.. Kupffer cell blockade, tumour necrosis factor secretion and survival following endotoxin challenge in experimental biliary obstruction.  Br J Surg. 1999;  86(11) 1410-1414
    CrossrefPubMedGoogle Scholar
  • 47 Ito Y, Bethea N W, Baker G L, McCuskey M K, Urbaschek R, McCuskey R S. Hepatic microcirculatory dysfunction during cholestatic liver injury in rats.  Microcirculation. 2003;  10(5) 421-432
    PubMedGoogle Scholar
  • 48 Gehring S, Dickson E M, San Martin M E et al.. Kupffer cells abrogate cholestatic liver injury in mice.  Gastroenterology. 2006;  130(3) 810-822
    CrossrefPubMedGoogle Scholar
  • 49 Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver.  Am J Physiol. 1991;  260(3 Pt 1) G355-G362
    PubMedGoogle Scholar
  • 50 Melgert B N, Olinga P, Van Der Laan J M et al.. Targeting dexamethasone to Kupffer cells: effects on liver inflammation and fibrosis in rats.  Hepatology. 2001;  34(4 Pt 1) 719-728
    CrossrefPubMedGoogle Scholar
  • 51 Canbay A, Feldstein A E, Higuchi H et al.. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.  Hepatology. 2003;  38(5) 1188-1198
    CrossrefPubMedGoogle Scholar
  • 52 Minter R M, Fan M H, Sun J et al.. Altered Kupffer cell function in biliary obstruction.  Surgery. 2005;  138(2) 236-245
    CrossrefPubMedGoogle Scholar
  • 53 Kim N D, Moon J O, Slitt A L, Copple B L. Early growth response factor-1 is critical for cholestatic liver injury.  Toxicol Sci. 2006;  90(2) 586-595
    PubMedGoogle Scholar
  • 54 Allen K, Kim N D, Moon J O, Copple B L. Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling.  Toxicol Appl Pharmacol. 2010;  243(1) 63-67
    CrossrefPubMedGoogle Scholar
  • 55 Jaeschke H. Enhanced sinusoidal glutathione efflux during endotoxin-induced oxidant stress in vivo.  Am J Physiol. 1992;  263(1 Pt 1) G60-G68
    PubMedGoogle Scholar
  • 56 Bilzer M, Lauterburg B H. Effects of hypochlorous acid and chloramines on vascular resistance, cell integrity, and biliary glutathione disulfide in the perfused rat liver: modulation by glutathione.  J Hepatol. 1991;  13(1) 84-89
    CrossrefPubMedGoogle Scholar
  • 57 Gujral J S, Hinson J A, Farhood A, Jaeschke H. NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia.  Am J Physiol Gastrointest Liver Physiol. 2004;  287(1) G243-G252
    CrossrefPubMedGoogle Scholar
  • 58 Hasegawa T, Malle E, Farhood A, Jaeschke H. Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning.  Am J Physiol Gastrointest Liver Physiol. 2005;  289(4) G760-G767
    PubMedGoogle Scholar
  • 59 Lehnert M, Arteel G E, Smutney O M et al.. Dependence of liver injury after hemorrhage/resuscitation in mice on NADPH oxidase-derived superoxide.  Shock. 2003;  19(4) 345-351
    CrossrefPubMedGoogle Scholar
  • 60 Jaeschke H, Ho Y S, Fisher M A, Lawson J A, Farhood A. Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress.  Hepatology. 1999;  29(2) 443-450
    CrossrefPubMedGoogle Scholar
  • 61 Jaeschke H. Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions.  Am J Physiol Gastrointest Liver Physiol. 2006;  290(6) G1083-G1088
    CrossrefPubMedGoogle Scholar
  • 62 Soylu A R, Aydogdu N, Basaran U N et al.. Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats.  World J Gastroenterol. 2006;  12(42) 6835-6841
    PubMedGoogle Scholar
  • 63 Parola M, Pinzani M, Casini A et al.. Induction of procollagen type I gene expression and synthesis in human hepatic stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenals is related to their molecular structure.  Biochem Biophys Res Commun. 1996;  222(2) 261-264
    CrossrefPubMedGoogle Scholar
  • 64 Bataller R, Schwabe R F, Choi Y H et al.. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis.  J Clin Invest. 2003;  112(9) 1383-1394
    PubMedGoogle Scholar
  • 65 Barón V, Muriel P. Role of glutathione, lipid peroxidation and antioxidants on acute bile-duct obstruction in the rat.  Biochim Biophys Acta. 1999;  1472(1-2) 173-180
    PubMedGoogle Scholar
  • 66 Sokol R J, Heubi J E, McGraw C, Balistreri W F. Correction of vitamin E deficiency in children with chronic cholestasis. II. Effect on gastrointestinal and hepatic function.  Hepatology. 1986;  6(6) 1263-1269
    CrossrefPubMedGoogle Scholar
  • 67 Yang Y Y, Lee K C, Huang Y T et al.. Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis.  J Hepatol. 2008;  49(1) 25-33
    CrossrefPubMedGoogle Scholar
  • 68 Tahan G, Tarcin O, Tahan V et al.. The effects of N-acetylcysteine on bile duct ligation-induced liver fibrosis in rats.  Dig Dis Sci. 2007;  52(12) 3348-3354
    CrossrefPubMedGoogle Scholar
  • 69 Gonzalez-Correa J A, De La Cruz J P, Martin-Aurioles E, Lopez-Egea M A, Ortiz P, Sanchez de la Cuesta F. Effects of S-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats.  Hepatology. 1997;  26(1) 121-127
    PubMedGoogle Scholar
  • 70 Yang H, Ramani K, Xia M et al.. Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications.  Hepatology. 2009;  49(6) 1982-1991
    CrossrefPubMedGoogle Scholar
  • 71 Zhong Z, Froh M, Lehnert M et al.. Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats.  Am J Physiol Gastrointest Liver Physiol. 2003;  285(5) G1004-G1013
    PubMedGoogle Scholar
  • 72 Zhong Z, Froh M, Wheeler M D, Smutney O, Lehmann T G, Thurman R G. Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat.  Gene Ther. 2002;  9(3) 183-191
    CrossrefPubMedGoogle Scholar
  • 73 Jaeschke H. Mechanisms of oxidant stress-induced acute tissue injury.  Proc Soc Exp Biol Med. 1995;  209(2) 104-111
    PubMedGoogle Scholar
  • 74 Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury.  J Gastroenterol Hepatol. 2000;  15(7) 718-724
    CrossrefPubMedGoogle Scholar
  • 75 Rehman H, Ramshesh V K, Theruvath T P et al.. NIM811 (N-methyl-4-isoleucine cyclosporine), a mitochondrial permeability transition inhibitor, attenuates cholestatic liver injury but not fibrosis in mice.  J Pharmacol Exp Ther. 2008;  327(3) 699-706
    CrossrefPubMedGoogle Scholar

Curtis D KlaassenPh.D. 

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center

4099 KLSIC, 3901 Rainbow Boulevard, Kansas City, KS 66160

Email: cklaasse@kumc.edu

      >