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Alcohol, oxidative stress and free radical damage

Published online by Cambridge University Press:  07 March 2007

Emanuele Albano*
Department of Medical Sciences, University of ‘A. Avogadro’ East Piedmont, Novara, Italy
Corresponding author: Professor Emanuele Albano, fax +39 0321 620421, email
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The involvement of free radical mechanisms in the pathogenesis of alcoholic liver disease (ALD) is demonstrated by the detection of lipid peroxidation markers in the liver and the serum of patients with alcoholism, as well as by experiments in alcohol-feed rodents that show a relationship between alcohol-induced oxidative stress and the development of liver pathology. Ethanol-induced oxidative stress is the result of the combined impairment of antioxidant defences and the production of reactive oxygen species by the mitochondrial electron transport chain, the alcohol-inducible cytochrome P450 (CYP) 2E1 and activated phagocytes. Furthermore, hydroxyethyl free radicals (HER) are also generated during ethanol metabolism by CYP2E1. The mechanisms by which oxidative stress contributes to alcohol toxicity are still not completely understood. The available evidence indicates that, by favouring mitochondrial permeability transition, oxidative stress promotes hepatocyte necrosis and/or apoptosis and is implicated in the alcohol-induced sensitization of hepatocytes to the pro-apoptotic action of TNF-α. Moreover, oxidative mechanisms can contribute to liver fibrosis, by triggering the release of pro-fibrotic cytokines and collagen gene expression in hepatic stellate cells. Finally, the reactions of HER and lipid peroxidation products with hepatic proteins stimulate both humoral and cellular immune reactions and favour the breaking of self-tolerance during ALD. Thus, immune responses might represent the mechanism by which alcohol-induced oxidative stress contributes to the perpetuation of chronic hepatic inflammation. Together these observations provide a rationale for the possible clinical application of antioxidants in the therapy for ALD.

Satellite Symposium on ‘Fish oils: a parenteral perspective’
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Adachi, M, Higuchi, H, Miura, S, Azuma, T, Inokuchi, S, Saito, H, Kato, S & Ishii, H (2004) Bax interacts with voltage-dependent anion channel and mediates ethanol-induced apoptosis in rat hepatocytes. American Journal of Physiology 287 G695G705.Google ScholarPubMed
Adachi, M & Ishii, H (2002) Role of mitochondria in alcoholic liver injury. Free Radical Biology and Medicine 32 487491.CrossRefGoogle ScholarPubMed
Albano, E (2002) Free radicals and alcohol-induced liver injury. In Ethanol and the Liver, pp. 153190 [Sherman, CDIN, Preedy, VR and Watson, RR, editors]. London: Taylor and Francis.CrossRefGoogle Scholar
Albano, E, Clot, P, Morimoto, M, Tomasi, A, Ingelman-Sundberg, M & French, SW (1996) Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radicals in the development of liver damage in rats intragastrically fed with ethanol. Hepatology 23 155163.CrossRefGoogle ScholarPubMed
Albano, E, Mottaran, E, Vidali, M, Vidali, M, Reale, E, Saksena, S, Occhino, D, Burt, AD & Day, CP (2005) Immune response toward lipid peroxidation products as a predictor of the progression of non-alcoholic fatty liver disease (NAFLD) to advanced fibrosis. Gut 54 987993.CrossRefGoogle Scholar
Albano, E, Parola, M, Comoglio, A & Dianzani, MU (1993) Evidence for the covalent binding of hydroxyethyl radicals to rat liver microsomal proteins. Alcohol and Alcoholism 28 453459.Google ScholarPubMed
Albano, E, Tomasi, A & Ingelman-Sundberg, M (1994) Spin trapping of alcohol-derived radicals in microsomes and reconstituted systems by electron spin resonance. Methods in Enzymology 233 117127.CrossRefGoogle ScholarPubMed
Aleynik, SI, Leo, MA, Aleynik, MK & Lieber, CS (1998) Increased circulating products of lipid peroxidation in patients with alcoholic liver disease. Alcoholism, Clinical and Experimental Research 22 192196.CrossRefGoogle ScholarPubMed
Arteel, GE (2003) Oxidant and antioxidant in alcohol-induced liver disease. Gastroenterology 124 778790.CrossRefGoogle ScholarPubMed
Bailey, SM & Cunningham, CC (2002) Contribution of mitochondria to oxidative stress associated with alcohol liver disease. Free Radical Biology and Medicine 32 1116.CrossRefGoogle Scholar
Bardag-Gorce, F, Yuan, QX, Li, J, French, BA, Fang, C, Ingelman-Sundberg, M & French, SW (2000) The effect of ethanol-induced cytochrome P4502E1 on the inhibition of proteasome activity by alcohol. Biochemical and Biophysical Research Communications 279 2329.CrossRefGoogle Scholar
Batey, RG, Cao, Q & Gould, B (2002) Lymphocyte-mediated liver injury in alcohol-related hepatitis. Alcohol 27 3741.CrossRefGoogle ScholarPubMed
Battaler, R & Brenner, DA (2005) Liver fibrosis. Journal of Clinical Investigation 115 209218.CrossRefGoogle Scholar
Bautista, AP (2002) Neutrophilic infiltration in alcoholic hepatitis. Alcohol 27 1721.CrossRefGoogle ScholarPubMed
Bautista, AP & Spitzer, JJ (1994) Inhibition of nitric oxide formation in vivo enhances superoxide release by the perfused liver. American Journal of Physiology 266 G783G788.Google ScholarPubMed
Bautista, AP & Spitzer, JJ (1996) Postbinge effects of acute alcohol intoxication on hepatic free radical formation. Alcoholism, Clinical and Experimental Research 20 502509.CrossRefGoogle ScholarPubMed
Beckman, JS & Koppenol, WH (1996) Nitric oxide, superoxide and peroxynitrite: the good, the bad and the ugly. American Journal of Physiology 271 C1424C1437.CrossRefGoogle ScholarPubMed
Bell, H, Bjørneboe, A, Eidsvoll, B, Norum, KR, Raknerud, N, Try, K, Thomansen, Y & Drevon, CA (1992) Reduced concentration of hepatic α-tocopherol in patients with alcoholic liver cirrhosis. Alcohol and Alcoholism 27 3946.Google ScholarPubMed
Bernardi, P, Petronilli, V, Di Lisa, F & Forte, M (2001) A mitochondrial perspective on cell death. Trends in Biochemical Sciences 26 112117.CrossRefGoogle ScholarPubMed
Bradford, BU, Kona, H, Isayama, F, Kosyk, O, Wheeler, MD, Akiyama, TE, Bleye, L, Krausz, KW, Gonzalez, FJ, Koop, DR & Rusyn, I (2005) Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase is required for ethanol-induced oxidative DNA damage in rodent liver. Hepatology 41 336344.CrossRefGoogle Scholar
Brind, AM, Hurlstone, A, Edrisinghe, D, Gilmore, I, Fisher, N, Pirmohamed, M & Fryer, AA (2004) The role of polymorphisms of glutathione S-transferases GSTM1, M3, P1, T1 and A1 in susceptibility to alcoholic liver disease. Alcohol and Alcoholism 39 478483.CrossRefGoogle ScholarPubMed
Canbay, A, Feldstein, AE, Higuchi, H, Werneburg, N, Grambihler, A, Bronk, SF & Gores, GJ (2003) Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38 11881198.CrossRefGoogle ScholarPubMed
Caro, AA & Cederbaum, AI (2004) Oxidative stress, toxicology and pharmacology of CYP2E1. Annual Review of Pharmacology and Toxicology 44 2742.CrossRefGoogle ScholarPubMed
Chamulitrat, W & Spitzer, JJ (1996) Nitric oxide and liver injury in alcohol-fed rats after lipipolysaccaride administration. Alcoholism, Clinical and Experimental Research 20 10651070.CrossRefGoogle ScholarPubMed
Chedid, A, Mendenhall, CL, Moritz, TE, French, SA, Chen, TS & Morgan, TR, et al. (1993) Cell-mediated hepatic injury in alcoholic liver disease. Veterans Affairs Cooperative Study Group 275. Gastroenterology 105 254266.CrossRefGoogle ScholarPubMed
Child, CG & Turcotte, JG (1964) Surgery and portal hypertension. In The Liver and Portal Hypertension, pp. 5064 [Child, CG, editor]. Philadelphia, PA: Saunders.Google ScholarPubMed
Clot, P, Albano, E, Elliasson, E, Tabone, M, Aricò, S, Israel, Y, Moncada, Y & Ingelman-Sundberg, M (1996) Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigenic determinant for autoantibody formation among alcoholics. Gastroenterology 111 206216.CrossRefGoogle ScholarPubMed
Clot, P, Bellomo, G, Tabone, M, Aricò, S & Albano, E (1995) Detection of antibodies against proteins modified by hydroxyethyl free radicals in patients with alcoholic cirrhosis. Gastroenterology 108 201207.CrossRefGoogle ScholarPubMed
Clot, P, Parola, M, Bellomo, G, Dianzani, U, Carini, R, Tabone, M, Aricò, S, Ingelman-Sundberg, M & Albano, E (1997) Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol. Gastroenterology 113 265276.CrossRefGoogle Scholar
Clot, P, Tabone, M, Aricò, S & Albano, E (1994) Monitoring oxidative damage in patients with liver cirrhosis and different daily alcohol intake. Gut 35 16371643.CrossRefGoogle ScholarPubMed
Coll, O, Colell, A, Garcia-Ruiz, C, Kaplowitz, N & Fernandez-Checa, JC (2003) Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion. Hepatology 38 692702.CrossRefGoogle ScholarPubMed
Dandona, P, Aljada, A & Bandyopadhyay, A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends in Immunology 25 47.CrossRefGoogle ScholarPubMed
Di Luzio, NR (1963) Prevention of acute ethanol-induced fatty liver by antioxidants. Physiologist 6 169173.Google Scholar
Dupont, I, Lucas, D, Clot, P, Ménez, C & Albano, E (1998) Cytochrome P4502E1 inducibility and hydroxyethyl radical formation among alcoholics. Journal of Hepatology 28 564571.CrossRefGoogle ScholarPubMed
Egen, JG, Kuhns, MS & Allison, JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nature Immunology 3 611618.CrossRefGoogle ScholarPubMed
Fang, C, Lindros, KO, Badger, TM, Ronis, JJ & Ingelman-Sundberg, M (1998) Zonated expression of cytokines in rat liver: effect of chronic ethanol and cytochrome P4502E1 inhibitor, chlormethiazole. Hepatology 27 13041310.CrossRefGoogle Scholar
Felver, ME, Mezey, E, McGuire, M, Mitchell, MC, Herlong, HF, Veech, GA & Veech, RL (1990) Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. Alcohol, Clinical and Experimental Research 14 255259.CrossRefGoogle ScholarPubMed
Fernandez-Checa, JC, Garcia-Ruiz, C, Ookhtens, M & Kaplowitz, N (1991) Impaired uptake of glutathione by hepatic mitochondria from ethanol fed rats. Journal of Clinical Investigation 87 397405.CrossRefGoogle ScholarPubMed
Fernandez-Checa, JC & Kaplowitz, N (2005) Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicology and Applied Pharmacology 204 263273.CrossRefGoogle ScholarPubMed
French, SW, Benson, NC & Sun, PS (1984) Centrilobular liver necrosis induced by hypoxia in chronic ethanol-fed rats. Hepatology 4 912917.CrossRefGoogle ScholarPubMed
Friedman, SL (2003) Liver fibrosis: from bench to bedside. Journal of Hepatology 38, Suppl. 1 S38S53CrossRefGoogle ScholarPubMed
Fromenty, B, Grimbert, S, Mansouri, A, Beaugrand, M, Erlinger, S, Röting, A & Pessayre, D (1995) Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis. Gastroenterology 108 193200.CrossRefGoogle ScholarPubMed
Fromenty, B & Pessayre, D (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacology and Therapeutics 67 101154.CrossRefGoogle ScholarPubMed
Garcia-Ruiz, C, Colell, A, Paris, R & Fernandez-Checa, JC (2000) Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release and caspase activation. FASEB Journal 14 847850.CrossRefGoogle ScholarPubMed
Garcia-Ruiz, C, Morales, A, Ballesta, A, Rhodes, J, Kaplowitz, N & Fernandez-Checa, JC (1994) Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. Journal of Clinical Investigation 94 193201.CrossRefGoogle ScholarPubMed
Girre, C, Lucas, D, Hispard, E, Ménez, C, Dally, S & Ménez, JF (1994) Assessment of cytochrome P4502E1 induction in alcoholic patients by chlozoxazone pharmacokinetics. Biochemical Pharmacology 47 15031508.CrossRefGoogle ScholarPubMed
Gouillon, Z, Lucas, D, Li, J, Hagbjork, AL, French, BA, Fu, P, Fang, C, Ingelman-Sundberg, M, Donohue, TM & French, SW (2000) Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole. Proceedings of the Society for Experimental Biology and Medicine 224 302308.CrossRefGoogle ScholarPubMed
Green, DR & Kroemer, G (2004) The pathophysiology of mitochondrial cell death. Science 305 626629.CrossRefGoogle ScholarPubMed
Gregory, CD & Devitt, A (2004) The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically. Immunology 113 114.CrossRefGoogle ScholarPubMed
Herkel, J, Jagemann, B, Weigard, C, Garcia Lazaro, JF, Lueth, S, Kanzler, S, Blessing, M, Schmitt, E & Lohse, AW (2003) MCH class II-expressing hepatocytes function as antigen presenting cells and activate specific CD4 T lymphocytes. Hepatology 37 10791085.CrossRefGoogle Scholar
Hines, IN & Wheeler, MD (2004) Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis. American Journal of Physiology 287 G310G314.Google ScholarPubMed
Hirano, T, Kaplowitz, N, Kamimura, T, Tsukamoto, H & Fernandez-Checa, JC (1992) Hepatic mitochondrial GSH depletion and progression of experimental alcoholic liver disease in rats. Hepatology 16 14231428.CrossRefGoogle Scholar
Hoek, JB, Cahill, A & Pastorino, JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122 20492063.CrossRefGoogle ScholarPubMed
Hoek, JB & Pastorino, JG (2004) Cellular signalling mechanisms in alcoholic liver damage. Seminars in Liver Diseases 24 257272.CrossRefGoogle Scholar
Iimuro, Y, Bradford, BU, Yamashina, S, Rusyn, I, Nakagami, M, Enomoto, N, Kono, H, Frey, W, Forman, D, Brenner, D & Thurman, RG (2000) The glutathione precursor l -2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. Hepatology 31 391398.CrossRefGoogle ScholarPubMed
Ioannou, GN, Dominitz, JA, Weiss, NS, Haegerty, PJ & Wowdley, KV (2004) The effect of alcohol consumption on the prevalence of iron overload, iron deficiency and ion deficiency anemia. Gastroenterology 126 12931301.CrossRefGoogle Scholar
Irving, MG, Halliday, JW & Powell, LW (1988) Association between alcoholism and increased hepatic iron store. Alcoholism, Clinical and Experimental Research 12 712.CrossRefGoogle Scholar
Ishak, KG, Zimmerman, HJ & Ray, MB (1991) Alcoholic liver disease: pathology, pathogenetic and clinical aspects. Alcoholism, Clinical and Experimental Research 15 4566.CrossRefGoogle ScholarPubMed
Izumi, N, Sato, C, Hamusura, Y & Takeuchi, J (1985) Serum antibodies against alcohol-treated hepatocytes in patients with alcoholic liver diseases. Clinical and Experimental Immunology 61 585592.Google Scholar
Jaeschke, H (2002) Neutrophil-mediated tissue injury in alcoholic hepatitis. Alcohol 27 2327.CrossRefGoogle ScholarPubMed
Jarvelainen, HA, Fang, C, Ingelman-Sundberg, M & Lindros, KO (1999) Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines. Hepatology 29 15031510.CrossRefGoogle ScholarPubMed
Kagan, VE, Borisenko, GG, Serinkan, BF, Tyurina, YY, Tyurin, VA, Jiang, J, Liu, SX, Shvedova, AA, Fabisial, JP, Uthsaisang, W & Fadeel, B (2003) Appetizing rancidity of apoptotic cells for macrophages: oxidation, externalization and recognition of phosphatidylserine. American Journal of Physiology 285 L1L17.Google ScholarPubMed
Kamimura, S, Gall, K, Britton, SR, Bacon, BR, Triadafilopulos, G & Tsukamoto, H (1992) Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: Association of lipid peroxidation with liver fibrogenesis. Hepatology 16 448453.CrossRefGoogle ScholarPubMed
Kamimura, S & Tsukamoto, H (1995) Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease. Hepatology 21 13041309.Google Scholar
Kawase, T, Kato, S & Lieber, CS (1989) Lipid peroxidation and antioxidant defense systems in rat liver after chronic ethanol feeding. Hepatology 10 815821.CrossRefGoogle ScholarPubMed
Kessova, IG, Ho, YS, Thung, S & Cederbaum, AI (2003) Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology 38 11361145.CrossRefGoogle ScholarPubMed
Kita, H, Mackay, IR, Van de Water, J & Gershwin, EM (2001) The lymphoid liver: considerations on pathways to autoimmune injury. Gastroenterology 120 14851501.CrossRefGoogle ScholarPubMed
Knecht, KT, Adachi, Y, Bradfort, BU, Iimuro, Y, Kadiiska, M, Qun-Hui, X & Thurman, RG (1995) Free radical adducts in the bile of ras treated chronically with intragastric alcohol: inhibition by destruction of Kupffer cells. Molecular Pharmacology 47 10281034.Google Scholar
Kono, H, Arteel, GE, Rusyn, I, Sies, H & Thurman, RG (2001a) Ebselen prevents early alcohol-induced liver injury in rats. Free Radical Biology and Medicine 30 403411.CrossRefGoogle ScholarPubMed
Kono, H, Bradford, BU, Yin, M, Sulik, KK, Koop, DR & Peters, JM, et al. (1999) CYP2E1 is not involved in early alcohol-induced liver injury. American Journal of Physiology 277 G1259G1267.Google Scholar
Kono, H, Rusyn, I, Yin, M, Gabele, E, Yamashina, S & Dikalova, A, et al. (2000) NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. Journal of Clinical Investigation 106 867872.CrossRefGoogle ScholarPubMed
Kono, H, Uesugi, T, Froh, M, Rusyn, I, Bradford, BU & Thurman, RG (2001b) ICAM-1 is involved in the mechanism of alcohol-induced liver injury: studies with knockout mice. American Journal of Physiology 280 G1289G1295.Google ScholarPubMed
Levine, JS, Koh, JS, Subang, R & Rauch, J (1999) Apoptotic cells as immunogen and antigen in the anti-phospholipid syndrome. Experimental and Molecular Pathology 66 8298.CrossRefGoogle Scholar
Li, J & Billiar, TR (1999) Nitric Oxide. IV. Determinants of nitric oxide protection and toxicity in liver. American Journal of Physiology 276 G1069G1073.Google ScholarPubMed
Liangpunsakul, S, Kolwankar, D, Pinto, A, Gorski, CJ, Hall, SD & Chalasani, N (2005) Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics. Hepatology 41 11441150.CrossRefGoogle ScholarPubMed
McClain, CJ, Song, Z, Barve, SS, Hill, DB & Deaciuc, I (2004) Recent advances in alcoholic liver disease IV. Dysregulated cytokine metabolism in alcoholic liver disease. American Journal of Physiology 287 G497G502.Google ScholarPubMed
McFarlane, IG (2000) Autoantibodies in alcoholic liver disease. Addiction Research 5 141151.Google ScholarPubMed
McKim, SE, Gabele, E, Isayama, F, Lambert, JC, Tucker, LM, Wheeler, MD, Connor, HD, Mason, RP, Doll, MA, Hein, DW & Arteel, GE (2003) Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice. Gastroenterology 125 18341844.CrossRefGoogle ScholarPubMed
McVicker, BL, Tuma, DJ, Kubik, JA, Hindemith, AM, Baldwin, CR & Casey, CA (2002) The effect of ethanol on asialoglycoprotein receptor-mediated phagocytosis of apoptotic cells by rat hepatocytes. Hepatology 36 14781487.Google ScholarPubMed
Mansouri, A, Fromenty, B, Berson, A, Robin, MA, Grimbert, S, Beaugrand, M, Erlinger, S & Pessayre, D (1997) Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholics. Journal of Hepatology 27 96102.CrossRefGoogle Scholar
Matsuhashi, T, Karbowski, M, Liu, X, Usukura, J, Wozniak, M & Wakabayashi, T (1998) Complete suppression of ethanol-induced formation of megamitochondria by 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-1-oxyl (4-OH-TEMPO). Free Radical Biology and Medicine 24 139147.CrossRefGoogle Scholar
Meager, EA, Barry, OP, Burke, A, Lucey, MR, Lawson, JA, Rokach, J & FitzGerald, GA (1999) Alcohol-induced generation of lipid peroxidation products in humans. Journal of Clinical Investigation 104 805813.CrossRefGoogle Scholar
Mezey, E, Potter, JJ, Rennie-Tankersley, l, Caballeire, J & Pares, A (2004) A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. Journal of Hepatology 40 4046.CrossRefGoogle ScholarPubMed
Minagawa, M, Deng, Q, Liu, ZX, Tzukamoto, H & Dennert, G (2004) Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-α during alcohol consumption. Gastroenterology 126 13871399.CrossRefGoogle ScholarPubMed
Moncada, C, Torres, V, Vargese, E, Albano, E & Israel, Y (1994) Ethanol-derived immunoreactive species formed by free radical mechanisms. Molecular Pharmacology 46 786791.Google ScholarPubMed
Morgan, K, French, SW & Morgan, TR (2002) Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology 36 122134.CrossRefGoogle ScholarPubMed
Mottaran, E, Stewart, SF, Rolla, R, Vay, D, Cipriani, V, Moretti, MG, Vidali, M, Sartori, M, Rigamonti, C, Day, CP & Albano, E (2002) Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease. Free Radical Biology and Medicine 32 3848.CrossRefGoogle ScholarPubMed
Nakao, LS & Augusto, O (1998) Nucleic acid alkylation by free radical metabolites of ethanol. Formation of 8-(1-hydroxyethyl)guanine and 8-(2-hydroxyethyl)guanineadducts. Chemical Research in Toxicology 11 888894.CrossRefGoogle Scholar
Nanji, AA & French, SW (1989) Dietary linoleic acid is required for development of experimentally induced alcoholic liver disease. Life Sciences 44 223227.CrossRefGoogle Scholar
Nanji, AA, Greenberg, SS, Tahan, SR, Fogt, F, Loscalzo, J, Sadrzadeh, SMH, Xie, J & Stamler, JS (1995a) Nitric oxide production in experimental alcoholic liver disease in the rat: role in protection from injury. Gastroenterology 109 899907.CrossRefGoogle ScholarPubMed
Nanji, AA, Griniuviene, B, Sadrzadeh, SMH, Levitsky, S & McCully, JD (1995b) Effect of dietary fat and ethanol on antioxidant enzyme mRNA induction in rat liver. Journal of Lipid Research 36 736744.Google ScholarPubMed
Nanji, AA, Khwaja, S, Tahan, SR & Sadrzadeh, HSM (1994a) Plasma levels of a novel noncyclooxygenase-derived prostanoid (8-isoprostane) correlate with severity of liver injury in experimental alcoholic liver disease. Journal of Pharmacology and Experimental Therapeutics 269 12801285.Google ScholarPubMed
Nanji, AA, Miao, L, Thomas, P, Rahemtulla, T, Khwaja, S, Zhao, S, Peters, D, Tahan, SR & Dannenberg, AJ (1997) Enhanced cycloxygenase-2 gene expression in alcoholic liver disease in rats. Gastroenterology 112 943951.CrossRefGoogle Scholar
Nanji, AA, Sadrzadeh, SMH, Yang, EK, Fogt, F, Maydani, M & Dannenberg, AJ (1995b) Dietary saturated fatty acids: A novel treatment for alcoholic liver disease. Gastroenterology 109 547554.CrossRefGoogle ScholarPubMed
Nanji, AA, Yang, EK, Fogt, F, Sadrzadeh, SMH & Dannenberg, AJ (1996) Medium chain triglycerides and vitamin E reduce the severity of established experimental alcoholic liver disease. Journal of Pharmacology and Experimental Therapeutics 277 16941700.Google ScholarPubMed
Nanji, AA, Zhao, S, Sadrzadeh, SMH, Dannenberg, AJ, Tahan, SR & Waxman, DJ (1994b) Markedly enhanced cytochrome P4502E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-treated ethanol-fed rats. Alcoholism, Clinical and Experimental Research 18 12801285.CrossRefGoogle Scholar
Natori, S, Rust, C, Stadheim, LM, Srinivasan, A, Burgart, LJ & Gores, GJ (2001) Hepatocyte apoptosis is a pathological feature of human alcoholic hepatitis. Journal of Hepatology 34 248253.CrossRefGoogle ScholarPubMed
Neuberger, J, Crossley, IR, Saunders, JB, Davis, M, Portmann, B, Eddleston, ALWF & Williams, R (1984) Antibodies to alcohol altered liver cell determinants in patients with alcoholic liver disease. Gut 25 300304.CrossRefGoogle ScholarPubMed
Neve, EP & Ingelman-Sundberg, M (2001) Identification and characterization of a mitochondrial targeting signal in rat cytochrome P450 2E1 (CYP2E1). Journal of Biological Chemistry 276 1131711322.CrossRefGoogle Scholar
Niemelä, O, Parkkila, S, Ylä-Herttuala, S, Halsted, C, Witztum, JL, Lanca, A & Israel, Y (1994) Covalent protein adducts in the liver as a result of ethanol metabolism and lipid peroxidation. Laboratory Investigation 70 537546.Google ScholarPubMed
Niemelä, O, Parkkila, S, Ylä-Herttuala, S, Villanueva, J, Ruebner, B & Halsted, CH (1995) Sequential acetaldehyde production, lipid peroxidation and fibrogenesis in micropigs model of alcohol-induced liver disease. Hepatology 22 12081214.CrossRefGoogle ScholarPubMed
Nordmann, R, Ribière, C & Rouach, H (1992) Implication of free radical mechanisms in ethanol induced cellular injury. Free Radical Biology and Medicine 12 219240.CrossRefGoogle ScholarPubMed
Parola, M & Robino, G (2001) Oxidative stress-related molecules and liver fibrosis. Journal of Hepatology 35 297306.CrossRefGoogle ScholarPubMed
Polavarapu, R, Spitz, DR, Sim, JE, Follansbee, MH, Oberley, LW, Rahemtulla, A & Nanji, AA (1998) Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil. Hepatology 27 13171323.CrossRefGoogle ScholarPubMed
Rao, RK, Seth, A & Sheth, P (2004) Recent advances in alcoholic liver disease. I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. American Journal of Physiology 286 G881G884.Google ScholarPubMed
Rolla, R, Vay, D, Mottaran, E, Parodi, M, Traverso, N & Arico, S, et al. (2000) Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 31 878884.CrossRefGoogle ScholarPubMed
Ronis, MJJ, Butura, A, Sampey, BP, Prior, RL, Korourian, S, Albano, E, Ingelman-Sundberg, M, Petersen, DR & Badger, TM (2005) Effects of N-acetyl cysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. Free Radical Biology and Medicine 36 616630.Google Scholar
Ronis, MJJ, Hakkak, R, Korourian, S, Albano, E, Yoon, S, Ingelman-Sundberg, M, Lindros, KO & Badger, TM (2004) Alcoholic liver disease in rats fed ethanol as part of oral or intragastric low-carbohydrate diets. Experimental Biology and Medicine 229 351360.CrossRefGoogle ScholarPubMed
Ronis, MJJ, Lindros, KO & Ingelman-Sundberg, M (1996) The CYP2E family. In Cytochromes P450: Metabolic and Toxicological Aspects, pp. 211239 [Ioannides, C, editor]. Boca Raton, FL: CRC Press.Google Scholar
Rouach, H, Fattaccioli, V, Gentil, M, French, SW, Morimoto, M & Nordmann, R (1997) Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology. Hepatology 25 351355.CrossRefGoogle ScholarPubMed
Rouault, TA (2003) Hepatic iron overload in alcoholic liver disease: why does it occur and what is its role in pathogenesis. Alcohol 30 103106.CrossRefGoogle ScholarPubMed
Sadrzadeh, SMH, Hallaway, PE & Nanji, AA (1997) The long-acting parenteral iron chelator hydroxyethylstarch-desferoxamine fails to protect against alcohol-induced liver injury in rats. Journal of Pharmacology and Experimental Therapeutics 280 10381042.Google ScholarPubMed
Sadrzadeh, SMH, Meydani, M, Khettry, U & Nanji, AA (1995) High-dose vitamin E supplementation has no effect on ethanol-induced pathological liver injury. Journal of Pharmacology and Experimental Therapeutics 273 455460.Google ScholarPubMed
Sadrzadeh, SMH & Nanji, AA (1998) The 21-aminosterolid 16-desmethyl-tirilazad mesylate prevents necroinflammatory changes in experimental alcoholic liver disease. Journal of Pharmacology and Experimental Therapeutics 284 406412.Google ScholarPubMed
Sadrzadeh, SMH, Nanji, AA & Meydani, M (1994a) Effect of chronic ethanol feeding on plasma and liver α- and γ-tocopherol levels in normal and vitamin E-deficient rats. Biochemical Pharmacology 47 20052010.CrossRefGoogle ScholarPubMed
Sadrzadeh, SMH, Nanji, AA & Prince, PL (1994b) The oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one reduces hepatic free iron, lipid peroxidation and fat accumulation in chronically ethanol-fed rats. Journal of Pharmacology and Experimental Therapeutics 269 632636.Google ScholarPubMed
Safadi, R, Ohta, M, Alvarez, CE, Fiel, MI, Bansal, M, Mehal, WZ & Friedman, SL (2004) Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology 127 870882.CrossRefGoogle ScholarPubMed
Savill, J, Dransfield, I, Gregory, C & Haslett, C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Reviews Immunology 2 965975.CrossRefGoogle ScholarPubMed
Schneiderhan, W, Schmid-Kotsas, A, Zhao, J, Grunert, A, Nusslaer, A, Weidenbach, H, Menke, A, Schmid, RM, Adler, G & Bachem, MG (2001) Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis. Hepatology 34 729737.CrossRefGoogle ScholarPubMed
Sergent, O, Griffon, B, Morel, I, Chevanne, M, Dubus, MP, Cillard, P & Cillard, J (1997) Effect of nitric oxide on iron-mediated oxidative stress in primary hepatocyte culture. Hepatology 23 122127.CrossRefGoogle Scholar
Shulga, N, Hoek, JB & Pastorino, JG (2005) Elevated PTEN levels account for the increased sensitivity of ethanol-exposed cells to tumor necrosis factor-induced cytotoxicity. Journal of Biological Chemistry 280 94169424.CrossRefGoogle ScholarPubMed
Stewart, SF, Jones, DEJ, Vidali, M, Haugk, B, Brunt, AD, Albano, E & Day, CP (2004a) Correlation between antiCYP2E1 titre and lymphocyte infiltration in ALD–an autoimmune disease in some patients. Journal of Hepatology 40, Suppl. 1 176CrossRefGoogle Scholar
Stewart, SF, Leathart, JB, Chen, Y, Daly, AK, Rolla, R, Mottaran, E, Vay, D, Vidali, M, Day, CP & Albano, E (2002) Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or fibrosis. Hepatology 36 13551360.CrossRefGoogle ScholarPubMed
Stewart, SF, Vidali, M, Day, CP, Albano, E & Jones, DEJ (2004b) Oxidative stress as a trigger for cellular immune response in patients with alcoholic liver disease. Hepatology 39 197203.CrossRefGoogle ScholarPubMed
Stoyanovsky, DA & Cederbaum, AI (1998) ESR and HPLC-EC analysis of ethanol oxidation to 1-hydroxyethyl radical: rapid reduction and quantification of POBN and PBN nitroxides. Free Radical Biology and Medicine 25 536545.CrossRefGoogle ScholarPubMed
Stoyanovsky, DA, Wu, D & Cederbaum, AI (1998) Interaction of 1-hydroxyethyl radical with glutathione, ascorbic acid and α-tocopherol. Free Radical Biology and Medicine 24 132138.CrossRefGoogle ScholarPubMed
Sutton, A, Khoury, H, Prop-Buus, C, Cepanec, C, Pessayre, D & Degoul, F (2003) The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 13 145157.CrossRefGoogle ScholarPubMed
Suzuki, M, Fujimoto, Y, Suzuki, Y, Hosoki, Y, Saito, H, Nakayama, K, Ohtake, T & Kohgo, Y (2004) Induction of transferrin receptor by ethanol in rat primary hepatocyte culture. Alcoholism, Clinical and Experimental Research 28 98S105S.CrossRefGoogle ScholarPubMed
Takase, S, Tsutsumi, M, Kawahara, H, Takada, N & Takada, A (1993) The alcohol-altered liver membrane antibody and hepatitis C virus infection in the progression of alcoholic liver disease. Hepatology 17 913.CrossRefGoogle ScholarPubMed
Thiele, GM, Freeman, TK & Klassen, LW (2004) Immunological mechanisms of alcoholic liver disease. Seminar of Liver Diseases 24 273287.CrossRefGoogle Scholar
Thurman, RG (1998) Alcoholic liver injury involves activation of Kupffer cells by endotoxins. American Journal of Physiology 275 G605G611.Google Scholar
Tsukamoto, H, French, SW, Benson, N, Delgado, G, Rao, GA, Larkin, EC & Largman, C (1985) Severe and progressive steatosis and focal necrosis in rat liver induced by continuous intragastric infusion of ethanol and low fat diet. Hepatology 5 224232.CrossRefGoogle ScholarPubMed
Tsukamoto, H, Horne, W, Kamimura, S, Niemelä, O, Parkkila, S, Ylä-Herttuala, S & Brittenham, GM (1995) Experimental liver cirrhosis induced by alcohol and iron. Journal of Clinical Investigation 96 620630.CrossRefGoogle ScholarPubMed
Tsukamoto, H, Lin, M, Ohata, M, Giulivi, C, French, SW & Brittenham, G (1999) Iron primes hepatic macrophages for NF-κB activation in alcoholic liver injury. American Journal of Physiology 277 G1240G1250.Google ScholarPubMed
Uesugi, T, Froh, M, Arteel, GE, Bradford, BU & Thurman, RG (2001) Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34 101108.CrossRefGoogle ScholarPubMed
Van Pelt, FNAM, Straub, P & Manns, MP (1995) Molecular basis of drug-induced immunological liver injury. Seminars in Liver Diseases 15 283300.CrossRefGoogle ScholarPubMed
Vay, D, Rigamonti, C, Vidali, M, Mottaran, E, Alchera, E, Occhino, G, Sartori, M & Albano, E (2006) Anti-phospholipid antibodies associated with alcoholic liver disease target oxidized phosphatidylserine on apoptotic cell plasma membranes. Journal of Hepatology 44 183189.CrossRefGoogle ScholarPubMed
Vidali, M, Hidestrand, M, Eliasson, E, Mottaran, E, Reale, E, Rolla, R, Occhino, G, Albano, E & Ingelman-Sundberg, M (2004) Use of molecular simulation for mapping conformational CYP2E1 epitopes. Journal of Biological Chemistry 279 5094950955.CrossRefGoogle ScholarPubMed
Vidali, M, Stewart, SF, Rolla, R, Daly, AK, Chen, Y, Mottaran, E, Jones, DEJ, Leathart, JB, Day, CP & Albano, E (2003) Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Hepatology 37 277285.CrossRefGoogle ScholarPubMed
Wajant, H, Pfizenmaier, K & Scheurich, P (2003) Tumor necrosis factor signalling. Cell Death and Differentiation 10 4565.CrossRefGoogle Scholar
Wheeler, MD, Kono, H, Yin, M, Rusyn, I, Froh, M, Connor, HD, Mason, RP, Samulski, RJ & Thurman, RG (2001a) Delivery of Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats. Gastroenterology 120 12411250.CrossRefGoogle ScholarPubMed
Wheeler, MD, Nakagami, M, Bradford, BU, Uesugi, T, Mason, RP, Connor, HD, Dikalova, A, Kadiiska, M & Thurman, RG (2001b) Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. Journal of Biological Chemistry 276 3666436672.CrossRefGoogle ScholarPubMed
Yin, M, Bradford, BU, Wheeler, MD, Uesugi, T, Froh, M, Goyert, SM & Thurman, RG (2001) Reduced early alcohol-induced liver injury in CD14-deficient mice. Journal of Immunology 166 47374742.CrossRefGoogle ScholarPubMed
You, M & Crabb, DW (2004) Recent advances in alcoholic liver disease. II. Molecular mechanisms of alcoholic fatty liver. American Journal of Physiology 287 G1G6.Google ScholarPubMed
Zamara, E, Novo, E, Marra, F, Gentilini, A, Romanelli, RG & Caligiuri, A, et al. (2004) 4-Hydroxynonenenal as a selective pro-fibrogeneic stimulus for activated human hepatic stellate cells. Journal of Hepatology 40 6068.CrossRefGoogle ScholarPubMed
Ziegler-Heitbrock, HW (1995) Molecular mechanism in tolerance to lipopolysaccharide. Journal of Inflammation 45 1326.Google ScholarPubMed
Ziol, M, Tepper, M, Lohez, M, Arcangeli, G, Ganne, N, Christidis, C, Trinchet, JC, Beaugrand, M, Guillet, JG & Guettier, C (2001) Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis. Journal of Hepatology 34 254260.CrossRefGoogle ScholarPubMed