Abstract
The mechanisms by which alcohol causes cell injury are not clear. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol-elevated production of lipopolysaccharide (LPS) and TNFα and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other; however, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNFα toxicity and that oxidative stress, activation of p38 and JNK MAP kinases, and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNFα potentiated hepatotoxicity. This Review will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved including activation of the mitogen-activated kinase kinase kinase ASK-1 as a result of CYP2E1-derived reactive oxygen intermediates promoting dissociation of the inhibitory thioredoxin from ASK-1. This activation of ASK-1 is followed by activation of the mitogen-activated kinase kinases MKK3/MKK6 and MKK4/MMK7 and subsequently p38 and JNK MAP kinases. Synergistic toxicity occurs between CYP2E1 and the JNK1 but not the JNK2 isoform as JNK1 knockout mice are completely protected against CYP2E1 plus TNFα toxicity, elevated oxidative stress, and mitochondrial dysfunction. We hypothesize that similar interactions occur as a result of ethanol induction of CYP2E1 and TNFα.
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References
Albano E (2006) Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 65:278–290
Bondy SC (1992) Ethanol toxicity and oxidative stress. Toxicol Lett 63:231–242
Cederbaum AI (2001) Introduction serial review: alcohol, oxidative stress and cell injury. Free Radic Biol Med 31:1524–1526
Nordman R, Riviere C, Rouach H (1992) Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radic Biol Med 12:219–240
Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG (1994) Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 20:453–460
Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG (1997) Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26:1530–1537
Nanji AA, Khettry U, Sadrzadeh SM (1994) Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver disease. Proc Soc Exp Biol Med 205:243–247
Yin XM, Ding WX (2003) Death receptor activation-induced hepatocyte apoptosis and liver injury. Curr Mol Med 3:491–508
Rao RK, Seth A, Sheth P (2004) Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 286:G881–884
Su GL (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256–G265
Deaciuc IV, Nikolova-Karakashian M, Fortunato F, Lee EY, Hill DB, McClain CJ (2000) Apoptosis and dysregulated ceramide metabolism in a murine model of alcohol-enhanced lipopolysaccharide hepatotoxicity. Alcohol Clin Exp Res 24:1557–1565
Hansen J, Cherwitz DL, Allen JI (1994) The role of tumor necrosis factor-alpha in acute endotoxin-induced hepatotoxicity in ethanol-fed rats. Hepatology 20:461–474
Koteish A, Yang S, Lin H, Huang X, Diehl AM (2002) Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. J Biol Chem 277:13037–13044
Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H (2000) Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 32:1008–1017
Kono H, Rusyn I, Uesugi T, Yamashina S, Connor HD, Dikalova A, Mason RP, Thurman RG (2001) Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. Am J Physiol Gastrointest Liver Physiol 280:G1005–G1012
Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG (2000) NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 106:867–872
Yin M, Wheeler MD, Kono H, Bradford BU, Galluci RM, Luster MI, Thurman RG (1999) Essential role of TNFα in alcohol-induced liver injury in mice. Gastroenterology 117:942–952
Lieber CS (1997) Cytochrome P4502E1; its physiological and pathological role. Physiol Rev 77:517–544
Koop DR (1992) Oxidative and reductive metabolism by cytochrome P4502E1. FASEB J 6:724–730
Song BJ, Cederbaum AI, Koop DR, Ingelman-Sundberg M, Nanji A (1996) Ethanol-inducible cytochrome P450 (CYP2E1): Biochemistry, molecular biology and clinical relevance. Alcohol Clin Exp Res 20(Suppl):138A–146A
Lee SST, Buters JTM, Pineau T, Fernandez-Salguero P, Gonzalez FJ (1996) Role of CYP2E1 in the hepatototoxicity of acetaminophen. J Biol Chem 271:12063–1206
Ekstrom G, Ingelman-Sundberg M (1989) Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem Pharmacol 38:1313–1319
Gorsky LD, Koop DR, Coon MJ (1984) On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P450. J Biol Chem 259:6812–6817
Rashba-Step J, Turro NJ, Cederbaum AI (1993) Increased NADPH- and NADH-dependent production of superoxide and hydroxyl radical by microsomes after chronic ethanol treatment. Arch Biochem Biophys 300:401–408
Caro AA, Cederbaum AI (2004) Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 44:27–42
Guengerich FP, Kim DH, Iwasaki M (1991) Role of cytochrome P450 IIE1in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 4:168–179
Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7:599–612
Kang JS, Wanibuchi H, Morimura K, Gonzalez FJ, Fukushima S (2007) Role of CYP2E1 in diethylnitrosamine-induced hepatocarcinogenesis in vivo. Cancer Res 67:11141–11146
Ye Q, Lian F, Chavez PR, Chung J, Ling W, Qin H, Seitz HK, Wang SD (2012) Cytochrome P4502E1 inhibition prevents hepatic carcinogenesis induced by diethylitrosamine in alcohol-fed rats. Hepatobiliary Surg Nutr 1:5–18
Mueller S (2013) Pharmacological blockage of CYP2E1 and alcohol-mediated liver cancer: is the time ready? Chin J Cancer Res 25:269–271
Hodges NJ, Green RM, Chipman JK, Graham M (2007) Induction of DNA strand breaks and oxidative stress in HeLa cells by ethanol is dependent on CYP2E1 expression. Mutagenesis 22:189–194
Navasumrit P, Ward D, Dodd NJF, O’Connor JO (2000) Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure. Carcinogenesis 21:93–99
Kim YD, Eom SY, Ogawa M, Oyama T, Isse T, Kang JW, Zhang YW, Kawamoto T, Kim H (2007) Ethanol-induced oxidative DNA damage and CYP2E1 expression in liver tissue of ALDH2 knockout mice. J Occup Health 49:363–369
Kukielka E, Cederbaum AI (1992) The effect of ethanol consumption on NADH- and NADPH- dependent generation of reactive oxygen intermediates by isolated rat liver nuclei. Alcohol Alcohol 27:233–239
Bradford BU, Kono H, Isayama F, Kosyk O, Wheeler MD, Akiyama TE, Bleye L, Krausz K, 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 41:336–344
Wang Y, Millonig G, Nair J, Patsenker E, Stickel F, Mueller S, Bartsch H, Seitz HK (2009) Ethaol-induced cytochrome P4502E1 causes carcinogenic ethano-DNA lesions in alcoholic liver disease. Hepatology 50:453–461
Morimoto M, Zern MA, Hagbjork AL, Ingelman-Sundberg M, French SW (1994) Fish oil, alcohol and liver pathology: role of cytochrome P450 2E1. Proc Soc Exp Biol Med 207:197–205
Nanji AA, Zhao S, Sadrzadeh SMH, Dannenberg AJ, Tahan SR, Waxman DJ (1994) Markedly enhanced cytochrome P4502E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol Clin Exp Res 18:1280–1285
French SW, Wong K, Jui L, Albano E, Hagbjork AL, Ingelman-Sundberg M (1993) Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis. Exp Mol Pathol 58:61–75
Morimoto M, Hagbjork AL, Wan YJ, Fu PC, Clot P, Albano E, Ingelman-Sundberg M, French SW (1995) Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors. Hepatology 21:1610–1617
Gouillon Z, Lucas D, Li J, Hagbjork AL, French BA, Fu P, Fang C, Ingelman-Sundberg M, Donohue TM Jr, French SW (2000) Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole. Proc Soc Exp Biol Med 224:302–308
Morgan K, French SW, Morgan TR (2002) Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology 36:122–134
Bai JX, Cederbaum AI (2004) Adenovirus-mediated overexpression of CYP2E1 increases sensitivity of HepG2 cells to acetaminophen induced cytotoxicity. Mol Cell Biochem 262:165–176
Bai JX, Cederbaum AI (2006) Adenovirus-mediated expression of CYP2E1 produces liver toxicity in mice. Toxicol Sci 91:365–371
Kamimura S, Tsukamoto H (1995) Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease. Hepatology 22:1304–1309
Honchel R, Ray MB, Marsano L, Cohen D, Lee E, Shedlofsky S, McClain CJ (1992) Tumor necrosis factor in alcohol enhanced endotoxin liver injury. Alcohol Clin Exp Res 16:665–669
Purohit V, Brenner DA (2006) Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Hepatology 43:872–878
Tsukamoto H (2001) How is the liver primed or sensitized for alcoholic liver disease? Alcohol Clin Exp Res 25:171S–181S
Pastorino JG, Hoek JB (2000) Ethanol potentiates tumor necrosis factor-alpha cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology 31:1141–1152
Liu H, Jones BE, Bradham C, Czaja MJ (2002) Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-alpha. Am J Physiol Gastrointest Liver Physiol 282:G257–G266
Lu Y, Cederbaum AI (2006) Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: role of cytochrome P450 2E1 and 2A5. Hepatology 44:263–274
Lu Y, Wang X, Cederbaum AI (2005) Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole. Am J Physiol Gastrointest Liver Physiol 289:G308–G319
Wu D, Cederbaum AI (2008) Cytochrome P4502E1 sensitizes to tumor necrosis factor alpha-induced liver injury through activation of mitogen-activated protein kinases in mice. Hepatology 47:1005–1017
Wu D, Xu C, Cederbaum A (2009) Role of nitric oxide and nuclear factor-kappaB in the CYP2E1 potentiation of tumor necrosis factor alpha hepatotoxicity in mice. Free Radic Biol Med 46:480–491
Bailey SM (2003) A review of the role of reactive oxygen and nitrogen species in alcohol-induced mitochondrial dysfunction. Free Radic Res 37:585–596
Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122:2049–2063
Zhuge J, Cederbaum AI (2009) Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice. Free Radic Biol Med 46:406–413
McCubrey JA, Franklin RA (2006) Reactive oxygen intermediates and signaling through kinase pathways. Antioxid Redox Signal 8:1745–1748
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275:90–94
Bardag-Gorce F, French BA, Dedes J, Li J, French SW (2006) Gene expression patterns of the liver in response to alcohol: in vivo and in vitro models compared. Exp Mol Pathol 80:241–251
Li J, Bardag-Gorce FJ, Oliva J, Dedes J, French BA, French SW (2009) Gene expression modifications in the liver caused by binge drinking and S-adenosylmethionine feeding. The role of epigenetic changes. Genes Nutr 5:169–179
Aroor AR, James TT, Jackson DE, Shukla SD (2010) Differential changes in MAP kinases, histone modifications, and liver injury in rats acutely treated with ethanol. Alcohol Clin Exp Res 34:1543–1551
Pastorino JG, Shulga N, Hoek JB (2003) TNF-alpha-induced cell death in ethanol-exposed cells depends on p38 MAPK signaling but is independent of Bid and caspase-8. Am J Physiol Gastrointest Liver Physiol 285:G503–G516
Czaja MJ (2003) The future of GI and liver research: editorial perspectives. III. JNK/AP-1 regulation of hepatocyte death. Am J Physiol Gastrointest Liver Physiol 284:G875–G879
Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N (2006) c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 131:165–178
Matsuzawa A, Ichijo H (2008) Redox control of cell fate by MAP kinase: physiological roles of ASK-1MAP kinase pathway in stress signaling. Biochim Biophys Acta 1780:1325–1336
Kyraiakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathway activated by stress and inflammation. Physiol Rev 81:807–869
Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, Ichijo H (2007) Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1. Mol Cell Biol 27:8152–8163
Liu H, Nishitoh H, Ichijo H, Kyriakis M (2000) Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol 20:2198–2208
Wang X, Destrument A, Tournier C (2007) Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta 1773:1349–1357
Matsukawa J, Matsuzawa A, Takeda K, Ichijo H (2004) The ASK-1-MAP kinase cascades in mammalian stress response. J Biochem 136:261–265
Wu D, Cederbaum AI (2010) Activation of ASK-1 and downstream MAP kinases in cytochrome P4502E1 potentiated tumor necrosis factor alpha liver injury. Free Radic Biol Med 49:348–60
Wu D, Cederbaum AI (2009) Oxidative stress and alcoholic liver disease. Semin Liver Dis 29:141–154
Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai KS, Ogura K, Noguchi T, Karin M, Ichijo H, Omata M (2008) Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N—Terminal kinase activation. Gastroenterology 135:1311–132
Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252
Schwabe RF, Uchinami H, Qian T, Bennett BL, Lemasters JJ, Brenner DA (2004) Differential requirement for c-Jun NH2-terminal kinase in TNFα-and Fas-mediated apoptosis in hepatocytes. FASEB J 18:720–722
Liu H, Lo CR, Czaja MJ (2002) NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a stained activation of JNK and c-Jun. Hepatology 35:772–778
Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja M (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43:163–176
Liu J, Minemoto Y, Lin A (2004) C-Jun N-terminal kinase1 (JNK1) but not JNK2 is essential for TNFα-induced c-Jun kinase activation and apoptosis. Mol Cell Biol 24:10844–10856
Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ (2006) Tumor necrosis factor induced liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem 281:15258–15267
Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ (2009) Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 49:87–96
Eminel S, Klettner K, Roemer L, Herdegan T, Waetzig V (2004) JNK2 translocates to the mitochondria and mediates cytochrome release in PC12 cells in response to 6-hydroxydopamine. J Biol Chem 279:55385–55392
Wang X, Wu D, Yang L, Cederbaum AI (2011) Hepatotoxicity mediated by cytochrome P4502E plus TNFα occurs in cJun-N terminal kinase 2−/− but not in cJun-N terminal 1−/− mice. Hepatology 54:1753–1766
Dey A, Cederbaum AI (2006) Alcohol and oxidative liver injury. Hepatology 43:S63–S74
Cederbaum AI (2009) Nrf2 and antioxidant defense against CYP2E1 toxicity. Expert Opin Drug Metab Toxicol 5:1–22
Yang L, Wu D, Wang X, Cederbaum AI (2012) Cytochrome P4502E1, oxidative stress. JNK and autophagy in acute-alcohol-induced fatty liver. Free Radic Biol Med 53:1170–1180
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Studies from the author’s lab were supported by USPHS grants RO1 AA 018790 and R21 AA 021362 from The National Institute on Alcohol Abuse and Alcoholism.
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Cederbaum, A.I., Lu, Y., Wang, X., Wu, D. (2015). Synergistic Toxic Interactions Between CYP2E1, LPS/TNFα, and JNK/p38 MAP Kinase and Their Implications in Alcohol-Induced Liver Injury. In: Vasiliou, V., Zakhari, S., Seitz, H., Hoek, J. (eds) Biological Basis of Alcohol-Induced Cancer. Advances in Experimental Medicine and Biology, vol 815. Springer, Cham. https://doi.org/10.1007/978-3-319-09614-8_9
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