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DOI: 10.1055/s-0029-1214370
Oxidative Stress and Alcoholic Liver Disease
Publication History
Publication Date:
22 April 2009 (online)
ABSTRACT
Reactive oxygen species (ROS) are highly reactive molecules that are naturally generated in small amounts during the body's metabolic reactions and can react with and damage complex cellular molecules such as lipids, proteins, or DNA. This review describes pathways involved in ROS formation, why ROS are toxic to cells, and how the liver protects itself against ROS. Acute and chronic ethanol treatment increases the production of ROS, lowers cellular antioxidant levels, and enhances oxidative stress in many tissues, especially the liver. Ethanol-induced oxidative stress plays a major role in the mechanisms by which ethanol produces liver injury. Many pathways play a key role in how ethanol induces oxidative stress. This review summarizes some of the leading pathways and discusses the evidence for their contribution to alcohol-induced liver injury.
KEYWORDS
Oxidative stress - alcoholic liver injury - reactive oxygen species - free radicals - antioxidants
REFERENCES
- 1 Nordmann R, Ribiere C, Rouach H. Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radic Biol Med. 1992; 12 219-240
- 2 Bondy S C. Ethanol toxicity and oxidative stress. Toxicol Lett. 1992; 63 231-241
- 3 Cederbaum A I. Introduction-serial review: alcohol, oxidative stress and cell injury. Free Radic Biol Med. 2001; 31 1524-1526
- 4 Tsukamoto H, Lu S C. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J. 2001; 15 1335-1349
- 5 Ishii H, Kurose I, Kato S. Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress. J Gastroenterol Hepatol. 1997; 12 S272-S282
- 6 Arteel G E. Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology. 2003; 124 778-790
- 7 Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organisms. Physiol Rev. 1979; 59 527-605
- 8 Toyokuni S. Reactive oxygen species–induced molecular damage and its application in pathology. Pathol Int. 1999; 49 91-102
- 9 de Groot H. Reactive oxygen species in tissue injury. Hepatogastroenterology. 1994; 41 328-332
- 10 Nakazawa H, Genka C, Fujishima M. Pathological aspects of active oxygens/free radicals. Jpn J Physiol. 1996; 46 15-32
- 11 Halliwell B. Antioxidant defense mechanisms: From the beginning to the end. Free Radic Res. 1999; 31 261-272
- 12 Bailey S M, Cunningham C C. Contribution of mitochondria to oxidative stress associated with alcoholic liver disease. Free Radic Biol Med. 2002; 32 11-16
- 13 Adachi M, Ishii H. Role of mitochondria in alcoholic liver injury. Free Radic Biol Med. 2002; 32 487-491
- 14 Lieber C S. Cytochrome P450 2E1: Its physiological and pathological role. Physiol Rev. 1997; 77 517-544
- 15 Sultatos L G. Effects of acute ethanol administration on the hepatic xanthine dehydrogenase/xanthine oxidase system in the rat. J Pharmacol Exp Ther. 1988; 246 946-949
- 16 Rosen G M, Pou S, Ramos C L et al.. Free radicals and phagocytic cells. FASEB J. 1995; 9 200-209
- 17 McCord J M. Iron, free radicals, and oxidative injury. Semin Hematol. 1998; 35 5-12
- 18 Yu B P. Cellular defenses against damage from reactive oxygen species. Physiol Rev. 1994; 74 139-162
- 19 Fridovich I. Superoxide anion radical, superoxide dismutases, and related matters. J Biol Chem. 1997; 272 18515-18517
- 20 Polavarapu R, Spitz D R, Sim J E et al.. 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. 1998; 27 1317-1323
- 21 Fernandez–Checa J C, Kaplowitz N, Colell A, García–Ruiz C. Oxidative stress and alcoholic liver disease. Alcohol Health Res World. 1997; 21 321-324
- 22 Nanji A A, Hiller–Sturmhöfel S. Apoptosis and necrosis. Alcohol Health Res World. 1997; 21 325-330
- 23 Adachi Y, Bradford B U, Gao W, Bojes H K, Thurman R G. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology. 1994; 20 453-460
- 24 Iimuro Y, Gallucci R M, Luster M I, Kono H, Thurman R G. Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology. 1997; 26 1530-1537
- 25 Nanji A A, Khettry U, Sadrzadeh S M. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver disease. Proc Soc Exp Biol Med. 1994; 205 243-247
- 26 Kono H, Rusyn I, Uesugi T et al.. Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. Am J Physiol Gastrointest Liver Physiol. 2001; 280 G1005-G1012
- 27 Kono H, Rusyn I, Yin M et al.. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest. 2000; 106 867-872
- 28 Yin M, Wheeler M D, Kono H et al.. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999; 117 942-952
- 29 Uesugi T, Froh M, Arteel G E et al.. Delivery of IkappaB superrepressor gene with adenovirus reduces early alcohol–induced liver injury in rats. Hepatology. 2001; 34 1149-1157
- 30 Thurman R G. Mechanisms of hepatic toxicity. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol. 1998; 275 G605-G611
- 31 Wheeler M D, Kono H, Yin M et al.. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic Biol Med. 2001; 31 1544-1549
- 32 Takei Y, Arteel G E, Bergheim I et al.. Roles of Kupffer cells in alcoholic liver disease. Alcohol Clin Exp Res. 2006; 29 1116-1120
- 33 Chapman R W, Morgan M Y, Bell R, Sherlock S. Hepatic iron uptake in alcoholic liver disease. Gastroenterology. 1983; 84 143-147
- 34 Sergent O, Morel I, Cogrel P et al.. Increase in cellular pool of low-molecular-weight iron during ethanol metabolism in rat hepatocyte cultures: Relationship with lipid peroxidation. Biol Trace Elem Res. 1995; 47 185-192
- 35 Valerio Jr L G, Parks T, Petersen D R. Alcohol mediates increases in hepatic and serum nonheme iron stores in a rat model for alcohol-induced liver injury. Alcohol Clin Exp Res. 1996; 20 1352-1361
- 36 Stal P, Johansson I, Ingelman-Sundberg M, Hagen K, Hultcrantz R. Hepatotoxicity induced by iron overload and alcohol: studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation. J Hepatol. 1996; 25 538-546
- 37 Tsukamoto H, Horne W, Kamimura S et al.. Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest. 1995; 96 620-630
- 38 Tsukamoto H, Lin M, Ohata M et al.. Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am J Physiol. 1999; 277 G1240-G1250
- 39 She H, Xiong S, Lin M et al.. Iron activates NF-kappaB in Kupffer cells. Am J Physiol Gastrointest Liver Physiol. 2002; 283 G719-G726
- 40 Sadrzadeh S M, Nanji A A, Price P L. 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. J Pharmacol Exp Ther. 1994; 269 632-636
- 41 Cederbaum A I. Iron and CYP2E1-dependent oxidative stress and toxicity. Alcohol. 2003; 30 115-120
- 42 Albano E, Tomasi A, Goria-Gatti L, Dianzani M U. Spin trapping of free radical species produced during the microsomal metabolism of ethanol. Chem Biol Interact. 1988; 65 223-234
- 43 Knecht K T, Thurman R G, Mason R P. Role of superoxide and trace transition metals in the production of alpha-hydroxyethyl radical from ethanol by microsomes from alcohol dehydrogenase-deficient deer mice. Arch Biochem Biophys. 1993; 303 339-348
- 44 Rashba-Step J, Cederbaum A I. Generation of reactive oxygen intermediates by human liver microsomes in the presence of NADPH or NADH. Mol Pharmacol. 1994; 45 150-157
- 45 Albano E, Tomasi A, Persson J O et al.. Role of ethanol-inducible cytochrome P450 (P450IIE1) in catalysing the free radical activation of aliphatic alcohols. Biochem Pharmacol. 1991; 41 1895-1902
- 46 Knecht K T, Bradford B U, Mason R P, Thurman R G. In vivo formation of a free radical metabolite of ethanol. Mol Pharmacol. 1990; 38 26-30
- 47 Moncada C, Torres V, Varghese G, Albano E, Israel Y. Ethanol-derived immunoreactive species formed by free radical mechanisms. Mol Pharmacol. 1994; 46 786-791
- 48 Clot P, Bellomo G, Tabone M, Arico S, Albano E. Detection of antibodies against proteins modified by hydroxyethyl free radicals in patients with alcoholic cirrhosis. Gastroenterology. 1995; 108 201-207
- 49 Reinke L A. Spin trapping evidence for alcohol-associated oxidative stress. Free Radic Biol Med. 2002; 32 953-957
- 50 Fernandez-Checa J C, Ookhtens M, Kaplowitz N. Effects of chronic ethanol feeding on rat hepatocystic glutathione: relationship of cytosolic glutathione to efflux and mitochondrial sequestration. J Clin Invest. 1989; 83 1247-1252
- 51 Iimuro Y, Bradford B U, Yamashina S et al.. The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. Hepatology. 2000; 31 391-398
- 52 Oh S I, Kim C I, Chun H J, Park S C. Chronic ethanol consumption affects glutathione status in rat liver. J Nutr. 1998; 128 758-763
- 53 Garcia-Ruiz C, Morales A, Colell A et al.. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology. 1995; 21 207-214
- 54 Colell A, Garcia-Ruiz C, Miranda M et al.. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology. 1998; 115 1541-1551
- 55 Bailey S M, Patel V B, Young T A, Asayama K, Cunningham C C. Chronic ethanol consumption alters the glutathione/glutathione peroxidase-1 system and protein oxidation status in rat liver. Alcohol Clin Exp Res. 2001; 25 726-733
- 56 Deaciuc I V, Fortunato F, D'Souza N B et al.. Modulation of caspase-3 activity and Fas ligand mRNA expression in rat liver cells in vivo by alcohol and lipopolysaccharide. Alcohol Clin Exp Res. 1999; 23 349-356
- 57 Cunningham C C, Coleman W B, Spach P I. The effects of chronic ethanol consumption on hepatic mitochondrial energy metabolism. Alcohol Alcohol. 1990; 25 127-136
- 58 Sastre J, Manana J B, Alguacil P et al.. Chronic ethanol feeding causes oxidative stress in rat liver mitochondria: prevention by S-adenosyl methionine. Free Radic Res. 1999; 30 325-327
- 59 Boveris A, Fraga C G, Varsavsky A I, Koch O R. Increased chemiluminescence and superoxide production in the liver of chronically ethanol-treated rats. Arch Biochem Biophys. 1983; 227 534-541
- 60 Kukielka E, Dicker E, Cederbaum A I. Increased production of reactive oxygen species by rat liver mitochondria after chronic ethanol treatment. Arch Biochem Biophys. 1994; 309 377-386
- 61 Bailey S M, Cunningham C C. Acute and chronic ethanol increases reactive oxygen species generation and decreases viability in fresh, isolated rat hepatocytes. Hepatology. 1998; 28 1318-1326
- 62 Venkatraman A, Landar A, Davis A J et al.. Modification of the mitochondrial proteome in response to the stress of ethanol-dependent hepatotoxicity. J Biol Chem. 2004; 279 22092-22101
- 63 Mansouri A, Gaou I, De Kerguenec C et al.. An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice. Gastroenterology. 1999; 117 181-190
- 64 Demeilliers C, Maisonneuve C, Grodet A et al.. Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice. Gastroenterology. 2002; 123 1278-1290
- 65 Mansouri A, Fromenty B, Berson A et al.. Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients. J Hepatol. 1997; 27 96-102
- 66 Cahill A, Stabley G J, Wang X, Hoek J B. Chronic ethanol consumption causes alterations in the structural integrity of mitochondrial DNA in aged rats. Hepatology. 1999; 30 881-888
- 67 Kurose I, Higuchi H, Kato S et al.. Oxidative stress on mitochondria and cell membrane of cultured rat hepatocytes and perfused liver exposed to ethanol. Gastroenterology. 1997; 112 1331-1343
- 68 Higuchi H, Adachi M, Miura S, Gores G J, Ishii H. The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes. Hepatology. 2001; 34 320-328
- 69 Pastorino J G, Marcineviciute A, Cahill A, Hoek J B. Potentiation by chronic ethanol treatment of the mitochondrial permeability transition. Biochem Biophys Res Commun. 1999; 265 405-409
- 70 Cahill A, Cunningham C C, Adachi M et al.. Effects of alcohol and oxidative stress on liver pathology: the role of the mitochondrion. Alcohol Clin Exp Res. 2002; 26 907-915
- 71 Hoek J B, Cahill A, Pastorino J G. Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology. 2002; 122 2049-2063
- 72 Bailey S M. A review of the role of reactive oxygen and nitrogen species in alcohol-induced mitochondrial dysfunction. Free Radic Res. 2003; 37 585-596
- 73 Hon W M, Lee K H, Khoo H E. Nitric oxide in liver diseases: friend, foe, or just passerby?. Ann N Y Acad Sci. 2002; 962 275-295
- 74 Wang J F, Greenberg S S, Spitzer J J. Chronic alcohol administration stimulates nitric oxide formation in the rat liver with or without pretreatment by lipopolysaccharide. Alcohol Clin Exp Res. 1995; 19 387-393
- 75 Arteel G E, Kadiiska M B, Rusyn I et al.. Oxidative stress occurs in perfused rat liver at low oxygen tension by mechanisms involving peroxynitrite. Mol Pharmacol. 1999; 55 708-715
- 76 Nanji A A, Greenberg S S, Tahan S R et al.. Nitric oxide production in experimental alcoholic liver disease in the rat: role in protection from injury. Gastroenterology. 1995; 109 899-907
- 77 Nanji A A, Jokelainen K, Lau G K et al.. Arginine reverses ethanol-induced inflammatory and fibrotic changes in liver despite continued ethanol administration. J Pharmacol Exp Ther. 2001; 299 832-839
- 78 McKim S E, Gabele E, Isayama F et al.. Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice. Gastroenterology. 2003; 125 1834-1844
- 79 Venkatraman A, Shiva S, Davis A J et al.. Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide. Hepatology. 2003; 38 141-147
- 80 Venkatraman A, Shiva S, Wigley A et al.. The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice. Hepatology. 2004; 40 565-573
- 81 Donohue Jr T M, Zetterman R K, Tuma D J. Effect of chronic ethanol administration on protein catabolism in rat liver. Alcohol Clin Exp Res. 1989; 13 49-57
- 82 Donohue Jr T M, Zetterman R K, Zhang-Gouillon Z Q, French S W. Peptidase activities of the multicatalytic protease in rat liver after voluntary and intragastric ethanol administration. Hepatology. 1998; 28 486-491
- 83 Fataccioli V, Andraud E, Gentil M, French S W, Rouach H. Effects of chronic ethanol administration on rat liver proteasome activities: relationship with oxidative stress. Hepatology. 1999; 29 14-20
- 84 Bardag-Gorce F, Yuan Q X, Li J et al.. The effect of ethanol-induced cytochrome p4502E1 on the inhibition of proteasome activity by alcohol. Biochem Biophys Res Commun. 2000; 279 23-29
- 85 Gouillon Z, Lucas D, Li J et al.. Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole. Proc Soc Exp Biol Med. 2000; 224 302-308
- 86 Goasduff T, Cederbaum A I. NADPH-dependent microsomal electron transfer increases degradation of CYP2E1 by the proteasome complex: role of reactive oxygen species. Arch Biochem Biophys. 1999; 370 258-270
- 87 Roberts B J. Evidence of proteasome-mediated cytochrome P-450 degradation. J Biol Chem. 1997; 272 9771-9778
- 88 Bradford B U, Kono H, Isayama F et al.. Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver. Hepatology. 2005; 41 336-344
- 89 Niemela O. Distribution of ethanol-induced protein adducts in vivo: relationship to tissue injury. Free Radic Biol Med. 2001; 31 1533-1538
- 90 Niemela O, Parkkila S, Yla-Herttuala S et al.. Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease. Hepatology. 1995; 22 1208-1214
- 91 Albano E. Free radical mechanisms in immune reactions associated with alcoholic liver disease. Free Radic Biol Med. 2002; 32 110-114
- 92 Duryee M J, Willis M S, Freeman T L et al.. Mechanisms of alcohol liver damage: aldehydes, scavenger receptors, and autoimmunity. Front Biosci. 2004; 9 3145-3155
- 93 Tuma D J. Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radic Biol Med. 2002; 32 303-308
- 94 Worrall S, de Jersey J, Wilce P A. Comparison of the formation of proteins modified by direct and indirect ethanol metabolites in the liver and blood of rats fed the Lieber-DeCarli liquid diet. Alcohol Alcohol. 2000; 35 164-170
- 95 Willis M S, Klassen L W, Tuma D J, Sorrell M F, Thiele G M. Adduction of soluble proteins with malondialdehyde-acetaldehyde (MAA) induces antibody production and enhances T-cell proliferation. Alcohol Clin Exp Res. 2002; 26 94-106
- 96 Rolla R, Vay D, Mottaran E et al.. Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology. 2000; 31 878-884
- 97 Koop D R. Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J. 1992; 6 724-730
- 98 Yang C S, Yoo J S, Ishizaki H, Hong J Y. Cytochrome P450IIE1: roles in nitrosamine metabolism and mechanisms of regulation. Drug Metab Rev. 1990; 22 147-159
- 99 Ekstrom G, Ingelman-Sundberg M. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol inducible cytochrome P-450 (P-450IIE1). Biochem Pharmacol. 1989; 38 1313-1319
- 100 Song B J, Cederbaum A I, Koop D R, Ingelman-Sundberg M, Nanji A. Ethanol-inducible cytochrome P450 (CYP2E1): biochemistry, molecular biology and clinical relevance. Alcohol Clin Exp Res. 1996; 20 138A-146A
- 101 Castillo T, Koop D R, Kamimura S, Triadafilopoulos G, Tsukamoto H. Role of cytochrome P-450 2E1 in ethanol-, carbon tetrachloride- and iron-dependent microsomal lipid peroxidation. Hepatology. 1992; 16 992-996
- 102 Nanji A A, Zhao S, Sadrzadeh S M et al.. Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol Clin Exp Res. 1994; 18 1280-1285
- 103 French S W, Wong K, Jui L et al.. Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis. Exp Mol Pathol. 1993; 58 61-75
- 104 Morimoto M, Hagbjork A L, Wan Y J et al.. Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors. Hepatology. 1995; 21 1610-1617
- 105 Morgan K, French S W, Morgan T R. Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology. 2002; 36 122-134
- 106 Koop D R, Klopfenstein B, Iimuro Y, Thurman R G. Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1. Mol Pharmacol. 1997; 51 944-950
- 107 Kono H, Bradford B U, Yin M et al.. CYP2E1 is not involved in early alcohol-induced liver injury. Am J Physiol. 1999; 277 G1259-G1267
- 108 Caro A A, Cederbaum A I. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol. 2004; 44 27-42
- 109 Kessova I, Cederbaum A I. CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury. Curr Mol Med. 2003; 3 509-518
- 110 Honchel R, Ray M B, Marsano L et al.. Tumor necrosis factor in alcohol enhanced endotoxin liver injury. Alcohol Clin Exp Res. 1992; 16 665-669
- 111 Kamimura S, Tsukamoto H. Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease. Hepatology. 1995; 22 1304-1309
- 112 Tsukamoto H. How is the liver primed or sensitized for alcoholic liver disease?. Alcohol Clin Exp Res. 2001; 25 171S-181S
- 113 Purohit V, Brenner D A. Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Hepatology. 2006; 43 872-878
- 114 Pastorino J G, Hoek J B. Ethanol potentiates tumor necrosis factor-alpha cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology. 2000; 31 1141-1152
- 115 Liu H, Jones B E, Bradham C, Czaja M J. Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-alpha. Am J Physiol Gastrointest Liver Physiol. 2002; 282 G257-G266
- 116 Lu Y, Wang X, Cederbaum A I. Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole. Am J Physiol Gastrointest Liver Physiol. 2005; 289 G308-G319
- 117 Lu Y, Cederbaum A I. Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: role of cytochrome P450 2E1 and 2A5. Hepatology. 2006; 44 263-274
- 118 Wu D, Cederbaum A I. Cytochrome P4502E1 sensitizes to tumor necrosis factor alpha-induced liver injury through activation of mitogen-activeted protein kineses in mice. Hepatology. 2008; 47 1005-1017
- 119 Di Luzio N R, Hartman A D. Role of lipid peroxidation in the pathogenesis of the ethanol-induced fatty liver. Fed Proc. 1967; 26 1436-1442
- 120 Nanji A A, Yang E K, Fogt F, Sadrzadeh S M, Dannenberg A J. Medium chain triglycerides and vitamin E reduce the severity of established experimental alcoholic liver disease. J Pharmacol Exp Ther. 1996; 277 1694-1700
- 121 Kono H, Arteel G E, Rusyn I, Sies H, Thurman R G. Ebselen prevents early alcohol-induced liver injury in rats. Free Radic Biol Med. 2001; 30 403-411
- 122 Iimuro Y, Bradford B U, Yamashina S et al.. The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. Hepatology. 2000; 31 391-398
- 123 Wheeler M D, Kono H, Yin M et al.. Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats. Gastroenterology. 2001; 120 1241-1250
- 124 Nanji A A, Jokelainen K, Tipoe G L, Rahemtulla A, Dannenberg A J. Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. J Pharmacol Exp Ther. 2001; 299 638-644
- 125 Kessova I G, Ho Y, Thung S, Cederbaum A I. Alcohol-induced liver injury in mice lacking Cu, Zn- superoxide dismutase. Hepatology. 2003; 38 1136-1145
- 126 Clemens D L. Use of cultured cells to study alcohol metabolism. Alcohol Res Health. 2006; 29 291-295
- 127 Fink R, Clemens M R, Marjot D H et al.. Increased free-radical activity in alcoholics. Lancet. 1985; 2 291-294
- 128 Letteron P, Duchatelle V, Berson A et al.. Increased ethane exhalation, an in vivo index of lipid peroxidation, in alcohol-abusers. Gut. 1993; 34 409-414
- 129 Adachi J, Matsushita S, Yoshioka N et al.. Plasma phosphatidylcholine hydroperoxide as a new marker of oxidative stress in alcoholic patients. J Lipid Res. 2004; 45 967-971
- 130 Ohhira M, Ohtake T, Matsumoto A et al.. Immunohistochemical detection of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver diseases. Alcohol Clin Exp Res. 1998; 22 145S-149S
- 131 Meagher E A, Barry O P, Burke A et al.. Alcohol-induced generation of lipid peroxidation products in humans. J Clin Invest. 1999; 104 805-813
- 132 Thome J, Zhang J, Davids E et al.. Evidence for increased oxidative stress in alcohol-dependent patients provided by quantification of in vivo salicylate hydroxylation products. Alcohol Clin Exp Res. 1997; 21 82-85
- 133 Mutlu-Türkoğlu U, Dogru-Abbasoglu S, Aykac-Toker G et al.. Increased lipid and protein oxidation and DNA damage in patients with chronic alcoholism. J Lab Clin Med. 2000; 135 287-291
- 134 Tanner A R, Bantock I, Hinks L et al.. Depressed selenium and vitamin E levels in an alcoholic population: possible relationship to hepatic injury through increased lipid peroxidation. Dig Dis Sci. 1986; 31 1307-1312
- 135 Bell H, Bjorneboe A, Eidsvoll B et al.. Reduced concentration of hepatic α-tocopherol in patients with alcoholic cirrhosis. Alcohol Alcohol. 1992; 27 39-46
- 136 Seki S, Kitada T, Sakaguchi H, Nakatoni K, Wakasa K. Pathological significance of oxidative cellular damage in human alcoholic liver disease. Histopathology. 2003; 42 365-371
- 137 Pemberton P W, Smith A, Warnes T W. Non-invasive monitoring of oxidant stress in alcoholic liver disease. Scand J Gastroenterol. 2005; 40 1102-1108
- 138 Rolla R, Vay D, Mottaran E et al.. Anti-phospholipid antibodies associated with alcoholic liver disease specifically recognize oxidized phospholipids. Gut. 2001; 49 852-859
- 139 Vidali M, Hietale J, Occhino G et al.. Immune responses against oxidative stress-derived antigens are associated with increased circulating tumor necrosis factor-α in heavy drinkers. Free Radic Biol Med. 2008; 45 306-311
- 140 Albano E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc. 2006; 65 278-290
Arthur I CederbaumPh.D.
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine
One Gustave L. Levy Place, Box 1603, New York, NY 10029
Email: arthur.cederbaum@mssm.edu