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Synergistic Toxic Interactions Between CYP2E1, LPS/TNFα, and JNK/p38 MAP Kinase and Their Implications in Alcohol-Induced Liver Injury

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Book cover Biological Basis of Alcohol-Induced Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 815))

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

  1. Albano E (2006) Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 65:278–290

    Article  CAS  PubMed  Google Scholar 

  2. Bondy SC (1992) Ethanol toxicity and oxidative stress. Toxicol Lett 63:231–242

    Article  CAS  PubMed  Google Scholar 

  3. Cederbaum AI (2001) Introduction serial review: alcohol, oxidative stress and cell injury. Free Radic Biol Med 31:1524–1526

    Article  CAS  PubMed  Google Scholar 

  4. Nordman R, Riviere C, Rouach H (1992) Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radic Biol Med 12:219–240

    Article  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. Yin XM, Ding WX (2003) Death receptor activation-induced hepatocyte apoptosis and liver injury. Curr Mol Med 3:491–508

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. Su GL (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256–G265

    CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  Google Scholar 

  15. 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

    CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. Lieber CS (1997) Cytochrome P4502E1; its physiological and pathological role. Physiol Rev 77:517–544

    CAS  PubMed  Google Scholar 

  19. Koop DR (1992) Oxidative and reductive metabolism by cytochrome P4502E1. FASEB J 6:724–730

    CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. Caro AA, Cederbaum AI (2004) Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 44:27–42

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7:599–612

    Article  CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. 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

    PubMed Central  PubMed  Google Scholar 

  30. Mueller S (2013) Pharmacological blockage of CYP2E1 and alcohol-mediated liver cancer: is the time ready? Chin J Cancer Res 25:269–271

    PubMed Central  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Article  CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    CAS  PubMed  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. 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

    Article  CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. 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

    CAS  PubMed  Google Scholar 

  41. 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

    Article  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. Bai JX, Cederbaum AI (2006) Adenovirus-mediated expression of CYP2E1 produces liver toxicity in mice. Toxicol Sci 91:365–371

    Article  CAS  PubMed  Google Scholar 

  45. Kamimura S, Tsukamoto H (1995) Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease. Hepatology 22:1304–1309

    CAS  PubMed  Google Scholar 

  46. 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

    Article  CAS  PubMed  Google Scholar 

  47. Purohit V, Brenner DA (2006) Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Hepatology 43:872–878

    Article  CAS  PubMed  Google Scholar 

  48. Tsukamoto H (2001) How is the liver primed or sensitized for alcoholic liver disease? Alcohol Clin Exp Res 25:171S–181S

    Article  CAS  PubMed  Google Scholar 

  49. 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

    Article  CAS  PubMed  Google Scholar 

  50. 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

    CAS  PubMed  Google Scholar 

  51. 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

    Article  CAS  PubMed  Google Scholar 

  52. 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

    Article  CAS  PubMed  Google Scholar 

  53. 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

    Article  CAS  PubMed  Google Scholar 

  54. 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

    Article  CAS  PubMed  Google Scholar 

  55. 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

    Article  CAS  PubMed  Google Scholar 

  56. Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122:2049–2063

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. McCubrey JA, Franklin RA (2006) Reactive oxygen intermediates and signaling through kinase pathways. Antioxid Redox Signal 8:1745–1748

    Article  CAS  PubMed  Google Scholar 

  59. 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

    Article  CAS  PubMed  Google Scholar 

  60. 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

    Article  CAS  PubMed  Google Scholar 

  61. 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

    Article  PubMed Central  PubMed  Google Scholar 

  62. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. 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

    CAS  PubMed  Google Scholar 

  64. 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

    CAS  PubMed  Google Scholar 

  65. 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

    Article  CAS  PubMed  Google Scholar 

  66. 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

    Article  CAS  PubMed  Google Scholar 

  67. Kyraiakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathway activated by stress and inflammation. Physiol Rev 81:807–869

    Google Scholar 

  68. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Wang X, Destrument A, Tournier C (2007) Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta 1773:1349–1357

    Article  CAS  PubMed  Google Scholar 

  71. Matsukawa J, Matsuzawa A, Takeda K, Ichijo H (2004) The ASK-1-MAP kinase cascades in mammalian stress response. J Biochem 136:261–265

    Article  CAS  PubMed  Google Scholar 

  72. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Wu D, Cederbaum AI (2009) Oxidative stress and alcoholic liver disease. Semin Liver Dis 29:141–154

    Article  CAS  PubMed  Google Scholar 

  74. 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

    Article  CAS  PubMed  Google Scholar 

  75. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  CAS  PubMed  Google Scholar 

  76. 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

    CAS  PubMed  Google Scholar 

  77. 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

    Article  CAS  PubMed  Google Scholar 

  78. 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

    Article  CAS  PubMed  Google Scholar 

  79. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. 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

    Article  CAS  PubMed  Google Scholar 

  83. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Dey A, Cederbaum AI (2006) Alcohol and oxidative liver injury. Hepatology 43:S63–S74

    Article  CAS  PubMed  Google Scholar 

  85. Cederbaum AI (2009) Nrf2 and antioxidant defense against CYP2E1 toxicity. Expert Opin Drug Metab Toxicol 5:1–22

    Article  Google Scholar 

  86. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgement

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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Authors and Affiliations

  1. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, Box 1603, One Gustave L. Levy Place, New York, NY, 10029, USA

    Arthur I. Cederbaum, Yongke Lu, Xiaodong Wang & Defeng Wu

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  1. Arthur I. Cederbaum
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  2. Yongke Lu
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  3. Xiaodong Wang
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Correspondence to Arthur I. Cederbaum .

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Editors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA

    Vasilis Vasiliou

  2. Distilled Spirits Council of the United States, Washington, District of Columbia, USA

    Samir Zakhari

  3. Centre of Alcohol Research, University of Heidelberg, Germany and Salem Medical Centre, Heidelberg, Germany

    Helmut K. Seitz

  4. Department of Pathology, Anatomy, & Cell, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Jan B. Hoek

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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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