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Hepatology International

, Volume 3, Issue 4, pp 526–536 | Cite as

Role of free radicals in liver diseases

  • Pablo MurielEmail author
Review Article

Abstract

Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B1 consumption, cigarette smoking, and heavy drinking. Ischemia–reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

Keywords

Oxidative stress Liver damage Liver injury ROS RNS Cancer Fibrosis Paracetamol HCV 

Notes

Acknowledgments

The author expresses his gratitude to biologist Mario G. Moreno in the preparation of the figures, and Liseth Rubí and Aldaba Muruato for their careful review of the manuscript.

References

  1. 1.
    Tsukamoto H. Conceptual importance of identifying alcoholic liver disease as a lifestyle disease. J Gastroenterol 2007;42:603–609PubMedGoogle Scholar
  2. 2.
    Di Luzio NR. A mechanism of the acute ethanol-induced fatty liver and the modification of liver injury by antioxidants. Lab Invest 1966;15:50–63Google Scholar
  3. 3.
    Minicis S, Brenner DA. Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. J Gastroenterol Hepatol 2008;23:S98–S103PubMedGoogle Scholar
  4. 4.
    Nordmann R, Ribiere C, Rouach H. Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radic Biol Med 1992;12:219–240PubMedGoogle Scholar
  5. 5.
    Cederbaum AI. Microsomal generation of reactive oxygen species and their possible role in alcohol hepatotoxicity. Alcohol Alcohol 1991;1:S291–S296Google Scholar
  6. 6.
    Knecht KT, Adachi Y, Bradford BU, Iimuro Y, Kadiiska M, Xuang QH, et al. Free radical adducts in the bile of rats treated chronically with intragastric alcohol: inhibition by destruction of Kupffer cells. Mol Pharmacol 1995;47:1028–1034PubMedGoogle Scholar
  7. 7.
    Tsukamoto H, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 2001;15:1335–1349PubMedGoogle Scholar
  8. 8.
    Iimuro Y, Bradford BU, Yamashina S, Rusyn I, Nakagami M, Enomoto N, et al. The glutathione precursor l-2-oxothiazolidine-4-carboxilic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. Hepatology 2000;31:391–398PubMedGoogle Scholar
  9. 9.
    Morimoto M, Zern MA, Hagbjork AL, Ingelman-Sundberg M, French SW. Fish oil, alcohol, and liver pathology: role of cytochrome P450 2E1. Proc Soc Exp Biol Med 1994;207:197–205PubMedGoogle Scholar
  10. 10.
    Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med 2008;44:723–734PubMedGoogle Scholar
  11. 11.
    Nanji AA, Zhao S, Sadrzadeh SM, Dannenberg AJ, Tahan SR, Waxman DJ. Markedly enhanced cytochrome P450E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol Clin Exp Res 1994;18:1280–1285PubMedGoogle Scholar
  12. 12.
    Tsukamoto H, Horne W, Kamimura S, Niemelä O, Parkkila S, Ylä-Herttuala S, et al. Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 1995;96:620–630PubMedGoogle Scholar
  13. 13.
    Kessova IG, Ho YS, Thung S, Cederbaum AI. Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology 2003;38:1133–1145Google Scholar
  14. 14.
    Kessova IG, Cederbaum AI. Mitochondrial alterations in livers of Sod1−/− mice fed alcohol. Free Radic Biol Med 2007;42:1470–1480PubMedGoogle Scholar
  15. 15.
    Adachi M, Ishii H. Role of mitochondria in alcoholic liver injury. Free Radic Biol Med 2002;32:487–491PubMedGoogle Scholar
  16. 16.
    Bailey SM, Cunningham CC. Contribution of mitochondria to oxidative stress associated with alcoholic liver disease. Free Radic Biol Med 2002;32:11–16PubMedGoogle Scholar
  17. 17.
    Wu D, Cederbaum AI. Ethanol-induced apoptosis to stable HepG2 cell lines expressing human cytochrome P-4502E1. Alcohol Clin Exp Res 1999;23:67–76PubMedGoogle Scholar
  18. 18.
    Friedman SL. Hepatic stellate cells: protean multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88:125–172PubMedGoogle Scholar
  19. 19.
    Ankoma-Sey V, Matli M, Chang KB, Lalazar A, Donner DB, Wong L, et al. Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing. Oncogene 1988;17:115–121Google Scholar
  20. 20.
    Shackel N, Rockey D. In pursuit of the “Holy Grail”-stem cells, hepatic injury, fibrogenesis and repair. Hepatology 2005;41:16–18PubMedGoogle Scholar
  21. 21.
    Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrog Tissue Repair 2008;13:5–23Google Scholar
  22. 22.
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134:1655–1669PubMedGoogle Scholar
  23. 23.
    Muriel P. Cytokines in liver diseases. In Sahu S, editor. Hepatotoxicity: From Genomics to In Vitro and In Vivo Models. West Sussex, UK: Wiley; 2007. 371–389Google Scholar
  24. 24.
    Wu J, Zern MA. Hepatic stellate cells: a target for the treatment of liver fibrosis. J Gastroenterol 2000;35:665–672PubMedGoogle Scholar
  25. 25.
    Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 2003;112:1383–1394PubMedGoogle Scholar
  26. 26.
    Prosser CC, Yen RD, Wu J. Molecular therapy for hepatic injury and fibrosis: where are we? World J Gastroenterol 2006;12:509–515PubMedGoogle Scholar
  27. 27.
    Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K, et al. NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology 2005;41:1272–1281PubMedGoogle Scholar
  28. 28.
    Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of platelet-derived growth factor polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 1989;84:1786–1793PubMedGoogle Scholar
  29. 29.
    Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 1999;83:18–29PubMedGoogle Scholar
  30. 30.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108PubMedGoogle Scholar
  31. 31.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750PubMedGoogle Scholar
  32. 32.
    Dominguez-Malagon H, Gaytan-Graham S. Hepatocellular carcinoma: an update. Ultraestruct Pathol 2001;25:497–516Google Scholar
  33. 33.
    Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 2002;181–182:43–47PubMedGoogle Scholar
  34. 34.
    Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 2006;387:349–360PubMedGoogle Scholar
  35. 35.
    Marx J. Inflammation and cancer: the link grows stronger. Science 2004;36:966–1008Google Scholar
  36. 36.
    Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci USA 1988;85:2706–2708PubMedGoogle Scholar
  37. 37.
    Ames BN. Mutagenesis and carcinogenesis: endogenous and exogenous factors. Environ Mol Mutagen 1989;16:S66–S77Google Scholar
  38. 38.
    Troll W, Wiesner R. The role of oxygen radicals as a possible mechanism of tumor promotion. Annu Rev Pharmacol Toxicol 1985;25:509–528PubMedGoogle Scholar
  39. 39.
    Kuchino Y, Mori F, Kasai InoueH, Iwai S, Miura K. et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature 1987;327:77–79PubMedGoogle Scholar
  40. 40.
    Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 2006;387:346–360Google Scholar
  41. 41.
    Choi J, Ou JH. Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol 2006;290:847–851Google Scholar
  42. 42.
    Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001;61:4365–4370PubMedGoogle Scholar
  43. 43.
    Farinati F, Cardin R, Bortolami M. Hepatitis C virus: from oxygen free radicals to hepatocellular carcinoma. J Viral Hepat 2007;14:821–829PubMedGoogle Scholar
  44. 44.
    Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Piña E, Geller DA. Factors in the pathophysiology of the liver ischemia–reperfusion injury. J Surg Res 2008;147:153–159PubMedGoogle Scholar
  45. 45.
    Powner DJ. Factors during donor care that may affect liver transplantation outcome. Prog Transplant 2004;14:241–247PubMedGoogle Scholar
  46. 46.
    Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia–reperfusion injury. Am J Surg 2001;181:160–166PubMedGoogle Scholar
  47. 47.
    Henderson JM. Liver transplantation and rejection: an overview. Hepatogastroentelogy 1999;46(Suppl 2):1482–1484Google Scholar
  48. 48.
    de Groot H, Rauen U. Ischemia–reperfusion injury: processes in pathogenetic networks: a review. Transplant Proc 2007;39:481–484PubMedGoogle Scholar
  49. 49.
    Jaeschke H. Molecular mechanism of hepatic ischemia–reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003;284:G15–G26PubMedGoogle Scholar
  50. 50.
    Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deads? Hepatology 2006;43:S31–S44PubMedGoogle Scholar
  51. 51.
    Anaya-Prado R, Toledo-Pereyra LH, Lentsch AB, Ward PA. Ischemia/reperfusion injury. J Surg Res 2002;105:248–258PubMedGoogle Scholar
  52. 52.
    McCord JM. Oxygen-derived radicals: a link between reperfusion injury and inflammation. Fed Proc 1987;46:2402–2406PubMedGoogle Scholar
  53. 53.
    Selzner N, Rudiger H, Graf R, Clavien PA. Protective strategies against ischemic injury of the liver. Gastroenterology 2003;125:917–936PubMedGoogle Scholar
  54. 54.
    Caldwell-Kenkel J, Currin R, Tanaka Y, Thurman R, Lemasters J. Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion. Hepatology 1991;13:83–95PubMedGoogle Scholar
  55. 55.
    Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia–reperfusion injury in rat liver in vivo. Am J Physiol 1991;260:G355–G362PubMedGoogle Scholar
  56. 56.
    Adamson G, Billings R. Tumor necrosis factor induced oxidative stress in isolated mouse hepatocytes. Arch Biochem Biophys 1992;294:223–229PubMedGoogle Scholar
  57. 57.
    Jaeschke H, Mitchell J. Mitochondria and xanthine oxidase both generate reactive oxygen species after hypoxic damage in isolated perfused rat liver. Biochem Biophys Res Commun 1989;160:140–147PubMedGoogle Scholar
  58. 58.
    Nordstrom G, Seeman T, Hasselgren PO. Beneficial effect of allopurinol in liver ischemia. Surgery 1985;97:679–984PubMedGoogle Scholar
  59. 59.
    Kusumoto K, Morimoto T, Minor T, Uchino J, Isselhard W. Allopurinol effects in rat liver transplantation on recovery of energy metabolism and free radical-induced damage. Eur Surg Res 1995;27:285–291PubMedGoogle Scholar
  60. 60.
    Marubayashi S, Dohi K, Ochi K, Kawasaki T. Protective effects of free radical scavenger and antioxidant administration on ischemic liver cell injury. Transplant Proc 1987;19:1327–1328PubMedGoogle Scholar
  61. 61.
    Koeppel TA, Lehmann TG, Thies JC, Gehrcke R, Gebhard MM, Herfarth C, et al. Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation. Transplantation 1996;61:1397–1402PubMedGoogle Scholar
  62. 62.
    Mizoe A, Kondo S, Azuma T, Fujioka H, Tanaka K, Hashida M, et al. Preventive effects of superoxide dismutase derivatives modified with monosaccharides on reperfusion injury in rat liver transplantation. J Surg Res 1997;73:160–165PubMedGoogle Scholar
  63. 63.
    Younes M, Strubelt O. The involvement of reactive oxygen species in hypoxic injury to rat liver. Res Commun Chem Pathol Pharmacol 1988;59:369–381PubMedGoogle Scholar
  64. 64.
    Marubayashi S, Dohi K, Yamada K, Kawasaki T. Changes in the levels of endogenous coenzyme Q homologs, alpha-tocopherol, and glutathione in rat liver after hepatic ischemia and reperfusion, and the effect of pretreatment with coenzyme Q10. Biochim Biophys Acta 1984;797:1–9PubMedGoogle Scholar
  65. 65.
    Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364–1372PubMedGoogle Scholar
  66. 66.
    Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990;10:267–278PubMedGoogle Scholar
  67. 67.
    Jaeschke H, Bajt ML. Intracellular signaling mechanism of acetaminophen-induced liver cell death. Toxicol Sci 2006;89:31–41PubMedGoogle Scholar
  68. 68.
    Pascual C, González R, Armesto J, Muriel P. Effect of silymarin and silybinin on oxygen radicals. Drug Dev Res 1993;29:73–77Google Scholar
  69. 69.
    Muriel P, Garciapiña T, Pérez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol 1992;12:439–442PubMedGoogle Scholar
  70. 70.
    Polson J, Lee WM. American Association for the Study of Liver Diseases. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179–1197PubMedGoogle Scholar
  71. 71.
    Choi J, Ou JH. Mechanism of liver injury: III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol 2006;290:G847–G851PubMedGoogle Scholar
  72. 72.
    Kageyama F, Kobayashi Y, Kawasaki T, Toyokuni S, Uchida K, Nakamura H. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C. Am J Gastroenterol 2000;95:1041–1050PubMedGoogle Scholar
  73. 73.
    Jain SK, Pemberton PW, Smith A, McMahon RF, Burrows PC, Aboutwerat A, et al. Oxidative stress in chronic hepatitis C: not just a feature of late stage disease. J Hepatol 2002;36:805–811PubMedGoogle Scholar
  74. 74.
    Mahmood S, Kawanaka M, Kamei A, Izumi A, Nakata K, Niiyama G, et al. Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C. Antioxid Redox Signal 2004;6:19–24PubMedGoogle Scholar
  75. 75.
    Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, et al. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 1995;22:449–456PubMedGoogle Scholar
  76. 76.
    Higueras V, Raya A, Rodrigo JM, Serra MA, Roma J, Romero FJ. Interferon decreases serum lipid peroxidation products of hepatitis C patients. Free Radic Biol Med 1994;16:131–133PubMedGoogle Scholar
  77. 77.
    Mutlu-Turkoglu U, Ademoglu E, Turkoglu S, Badur S, Uysal M, Toker G. The effects of interferon-alpha on serum lipid peroxidation and total thiol content in patients with chronic active hepatitis-C. Res Commun Mol Pathol Pharmacol 1997;96:357–361PubMedGoogle Scholar
  78. 78.
    Swietek K, Juszczyk J. Reduced glutathione concentration in erythrocytes of patients with acute and chronic viral hepatitis. J Viral Hepat 1997;4:139–141PubMedGoogle Scholar
  79. 79.
    Konishi M, Iwasa M, Araki J. Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane. J Gastroenterol Hepatol 2006;21:1821–1825PubMedGoogle Scholar
  80. 80.
    Paradis V, Mathurin P, Kollinger M. In situ detection of lipid peroxidation in chronic hepatitis C: correlation with pathological features. J Clin Pathol 1997;50:401–406PubMedGoogle Scholar
  81. 81.
    Farinati F, Cardin R, Degan P, De Maria N, Floyd RA, Van Thiel DH, et al. Oxidative DNA damage in circulating leukocytes occurs as an early event in chronic HCV infection. Free Radic Biol Med 1999;27:1284–1291PubMedGoogle Scholar
  82. 82.
    Hara Y, Hino K, Okuda M, Furutani T, Hidaka I, Yamaguchi Y, et al. Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species. J Gastroenterol 2006;41:257–268PubMedGoogle Scholar
  83. 83.
    Seronello S, Sheikh MY, Choi J. Redox regulation of hepatitis C in nonalcoholic and alcoholic liver. Free Radic Biol Med 2007;43:869–882PubMedGoogle Scholar
  84. 84.
    Izumi N, Enomoto N, Uchihara M, Murakami T, Ono K, Noguchi O, et al. Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C: relationship to genotypes of hepatitis C virus. Dig Dis Sci 1996;41:989–994PubMedGoogle Scholar
  85. 85.
    Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med 2000;21:49–98PubMedGoogle Scholar
  86. 86.
    Koike N, Takamura T, Kaneko S. Induction of reactive species from isolated rat glomeruli by protein kinase C activation and TNF-alpha stimulation, and effects of a phosphodiesterase inhibitor. Life Sci 2007;80:1721–1728PubMedGoogle Scholar
  87. 87.
    Garcia-Trevijano ER, Iraburu MJ, Fontana L, Domínguez-Rosales JA, Auster A, Covarrubias-Pinedo A, et al. Transforming growth factor beta 1 induces the expression of alpha(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells. Hepatology 1999;29:910–960Google Scholar
  88. 88.
    Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to liver injury. J Biol Chem 2000;275:2247–2250PubMedGoogle Scholar
  89. 89.
    Kota RS, Ramana CV, Tenorio FA, Enelow RI, Rutledge JC. Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. J Biol Chem 2005;280:31076–31084PubMedGoogle Scholar
  90. 90.
    Liu C, Gaca MD, Swenson ES, Vellucci VF, Reiss M, Wells RG. Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta) in quiescent and activated hepatic stellate cells: constitutive nuclear localization of Smads in activated cells is TGF-beta-independent. J Biol Chem 2003;278:11721–11728PubMedGoogle Scholar
  91. 91.
    Korenagua M, Wang T, Li Y, Showalter LA, Chang T, Sun J, et al. Hepatitis virus core protein inhibits mitochondrial electron transport and increases ROS production. J Biol Chem 2005;280:37481–37488Google Scholar
  92. 92.
    Abdalla MY, Ahmad IM, Spitz DR, Schmidt WN, Britigan BE. Hepatitis C virus-core and non structural proteins lead to different effects on cellular antioxidant defenses. J Med Virol 2005;76:489–497PubMedGoogle Scholar
  93. 93.
    Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expressions are induced by hepatitis C core proteins. Gastroenterology 2002;122:366–375PubMedGoogle Scholar
  94. 94.
    Li K, Prow T, Lemon SM, Beard MR. Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells. Hepatology 2002;35:1237–1246PubMedGoogle Scholar
  95. 95.
    Perlemuter G, Letteron P, Carnot F, Zavala F, Pessayre D, Nalpas B, et al. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model. J Hepatol 2003;39:1020–1027PubMedGoogle Scholar
  96. 96.
    Li Y, Boehning DF, Qian T, Popov VL, Weinman SA. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J 2007;21:2474–2485PubMedGoogle Scholar
  97. 97.
    Gochee PA, Jonsson JR, Clouston AD, Pandeya N, Purdie DM, Powell EE. Steatosis in chronic hepatitis C: association with increased messenger RNA expression of collagen I, tumor necrosis factor-alpha and cytochrome P450 2E1. J Gastroenterol Hepatol 2003;18:386–392PubMedGoogle Scholar
  98. 98.
    de Lucas S, Bartolome J, Amaro MJ, Carreno V. Hepatitis C virus core protein transactivates the inducible nitric oxide synthase promoter via NF-kappaB activation. Antiviral Res 2003;60:117–124PubMedGoogle Scholar
  99. 99.
    Garcia-Mediavilla MV, Sanchez-Campos S, Gonzalez-Perez P, Gómez-Gonzalo M, Majano PL, López-Cabrera M, et al. Differential contribution of hepatitis C virus NS5A and core proteins to the induction of oxidative and nitrosative stress in human hepatocyte-derived cells. J Hepatol 2005;43:606–613PubMedGoogle Scholar
  100. 100.
    Waris G, Siddiqui A. Hepatitis C virus stimulates the expression of cyclooxigenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication. J Virol 2005;79:9725–9734PubMedGoogle Scholar
  101. 101.
    Nunez O, Fernandez-Martinez A, Majano PL, Apolinario A, Gómez-Gonzalo M, Benedicto I, et al. Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2 and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins. Gut 2004;53:1665–1672PubMedGoogle Scholar
  102. 102.
    Miller K, McArdle S, Gale MJ Jr, Geller DA, Tenoever B, Hiscott J, et al. Effects of the hepatitis C virus core protein on innate cellular defense pathways. J Interferon Cytokine Res 2004;24:391–402PubMedGoogle Scholar
  103. 103.
    Machida K, Cheng KT, Sung VM, Lee KJ, Levine AM, Lai MM. Hepatitis C virus infection activates the immunologic (type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. J Virol 2004;78:8835–8843PubMedGoogle Scholar
  104. 104.
    Gong G, Waris G, Tanveer R, Siddiqui A. Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proc Natl Acad Sci USA 2001;98:9599–9604PubMedGoogle Scholar
  105. 105.
    Qadri I, Iwahashi M, Capasso JM, Hopken MW, Flores S, Schaack J, et al. Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAPK and AP1. Biochem J 2004;378:919–928PubMedGoogle Scholar
  106. 106.
    Machida K, Cheng KT, Sung VM. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci USA 2004;101:4262–4267PubMedGoogle Scholar
  107. 107.
    Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 1998;4:1065–1067PubMedGoogle Scholar
  108. 108.
    Brune B. The intimate relation between nitric oxide and superoxide in apoptosis and cell survival. Antioxid Redox Signal 2005;7:497–507PubMedGoogle Scholar
  109. 109.
    Melhem A, Stern M, Shibolet O, Israeli E, Ackerman Z, Pappo O, et al. Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. J Clin Gastroenterol 2005;39:737–742PubMedGoogle Scholar
  110. 110.
    Lieber CS. CYP2E1 from ASH to NASH. Hepatol Res 2004;28:1–11PubMedGoogle Scholar
  111. 111.
    Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CY2P2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 2000;105:1067–1075PubMedGoogle Scholar
  112. 112.
    George J, Pera N, Phung N, Leclercq I, Yun Hou J, Farrell G. Lipid peroxidation stellate cells activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis. J Hepatol 2003;39:756–764PubMedGoogle Scholar
  113. 113.
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001;120:1183–1192PubMedGoogle Scholar
  114. 114.
    Garcia-Monson C, Martin Perez E, Lojacono O. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol 2000;33:716–724Google Scholar
  115. 115.
    Videla LA, Rodrigo R, Orelland M. Oxidation stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci 2004;106:261–268PubMedGoogle Scholar
  116. 116.
    Koruk M, Taysi S, Savas MC, Yilmaz O, Akcay F, Karakok M. Oxidative stress and enzymatic antioxidant status in patients with non alcoholic steatohepatitis. Ann Clin Lab Sci 2004;34:57–62PubMedGoogle Scholar
  117. 117.
    Loguercio C, De Girolamo V, de Sio I, Tuccillo C, Ascione A, Baldi F, et al. Non-alcoholic fatty liver disease in an area of southern Italy: main clinical histological, and pathophysiological aspects. J Hepatol 2001;35:568–574PubMedGoogle Scholar
  118. 118.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001;50:1844–1850PubMedGoogle Scholar
  119. 119.
    Nehra V, Angulo P, Buchman AL, Lindor KD. Nutritional and metabolic considerations in the etiology of non-alcoholic steatohepatitis. Dig Dis Sci 2001;46:2347–2352PubMedGoogle Scholar
  120. 120.
    Mavrelis PG, Ammon HV, Gleysteen JJ, Komorowski RA, Charaf UK. Hepatic free fatty acids in alcoholic liver disease and obesity. Hepatology 1983;3:226–231PubMedCrossRefGoogle Scholar
  121. 121.
    Clarke SD. Nonalcoholic steatosis and steatohepatitis, part I: molecular mechanism for polyunsaturated fatty acid regulation of gene transcription. Am J Physiol Gastrointest Liver Physiol 2001;281:G865–G869PubMedGoogle Scholar
  122. 122.
    Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol 2001;35:297–306PubMedGoogle Scholar
  123. 123.
    Goldstein BJ, Kalyankar M, Wu X. Insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. Diabetes 2005;54:311–321PubMedGoogle Scholar
  124. 124.
    Wanless JR, Bargman JM, Oreopoullos DG. Subcapsular steatonecrosis in response to peritoneal insulin deliver: a clue to the pathogenesis of steatonecrosis in obesity. Mod Pathol 1989;2:69–74PubMedGoogle Scholar
  125. 125.
    Khalili K, Lan FP, Hanbidge AE, Muradali D, Oreopoulos DG, Wanless IR. Hepatic subcapsular steatosis in response to intraperitoneal insulin delivery: CT findings and prevalence. AJR Am J Roentgenol 2003;180:1601–1604PubMedGoogle Scholar
  126. 126.
    Paradis V, Perlemuter G, Benvoust F, Dargere D, Parfait B, Vidaud M, et al. High glucose and hyperinsulinemia stimulate connective growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738–744PubMedGoogle Scholar
  127. 127.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413–1419PubMedGoogle Scholar
  128. 128.
    Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004;2:262–265PubMedGoogle Scholar
  129. 129.
    El-Serag HR, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460–468PubMedGoogle Scholar
  130. 130.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action and type 2 diabetes. Science 2004;306:457–461PubMedGoogle Scholar
  131. 131.
    Muoio DM. Insulin resistance takes a trip through the ER. Science 2004;306:4285–4426Google Scholar
  132. 132.
    George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998;114:311–318PubMedGoogle Scholar
  133. 133.
    Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, et al. Nonalcoholic steatohepatitis and iron increased prevalence of mutations of HFE gene in nonalcoholic steatohepatitis. J Hepatol 1999;31:421–429PubMedGoogle Scholar
  134. 134.
    Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–1109PubMedGoogle Scholar
  135. 135.
    Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–1362PubMedGoogle Scholar
  136. 136.
    Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O’Neill R, et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 1999;30:847–850PubMedGoogle Scholar
  137. 137.
    Chitturi S, Weltman M, Farrell GC, McDonald D, Kench J, Liddle C, et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002;36:142–149PubMedGoogle Scholar
  138. 138.
    Bugianesi E, Manzini P, D’Antico S, Vanni E, Longo F, Leone N, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004;39:179–187PubMedGoogle Scholar
  139. 139.
    Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D, Fociani P, et al. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am J Gastroenterol 2001;96:2448–2455PubMedGoogle Scholar
  140. 140.
    Fernández-Real JM, Ricart-Engel W, Arroyo E, Balançá R, Casamitjana-Abella R, Cabrero D, et al. Serum ferritin as a component of the insulin resistance syndrome. Diabetes Care 1998;21:62–68PubMedGoogle Scholar
  141. 141.
    Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999;117:1115–1163Google Scholar
  142. 142.
    Macdonald GA, Powell LW. More clues to the relationship between hepatic iron and steatosis: an association with insulin resistance? Gastroenterology 1999;117:1241–1244PubMedGoogle Scholar
  143. 143.
    Dinneen SF, Silverberg JD, Batts KP, O’Brien PC, Ballard DJ, Rizza RA. Liver iron stores in patients with non-insulin-dependent diabetes mellitus. Mayo Clin Proc 1994;69:13–15PubMedGoogle Scholar
  144. 144.
    Rauen U, Petrat F, Sustmann R, de Groot H. Iron-induced mitochondrial permeability transition in cultured hepatocytes. J Hepatol 2004;40:607–615PubMedGoogle Scholar
  145. 145.
    Bulteau AL, O’Neill HA, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science 2004;305:242–245PubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2009

Authors and Affiliations

  1. 1.Department of PharmacologyCinvestav-I.P.N.MexicoMexico

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