Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and mechanisms of liver injury induced by APAP overdose have been the focus of extensive investigation. Studies in the mouse model, which closely reproduces the human condition, have shown that hepatotoxicity is initiated by formation of a reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes cellular glutathione and forms protein adducts on mitochondrial proteins. This leads to mitochondrial oxi dative and nitrosative stress, accompanied by activation of c-jun N-terminal kinase (JNK) and its transloca tion to the mitochondria. This then amplifies the mitochondrial oxidant stress, resulting in translocation of Bax and dynamin related protein 1 (Drp1) to the mitochondria, which induces mitochondrial fission, and ultimately induction of the mitochondrial membrane permeability transition (MPT). The induction of MPT triggers release of intermembrane proteins such as apoptosis inducing factor (AIF) and endonuclease G into the cytosol and their translocation to the nucleus, causing nuclear DNA fragmentation and activation of regulated necrosis. Though these cascades of events were primarily identified in the mouse model, studies on human hepatocytes and analysis of circulating biomarkers from patients after APAP overdose, indicate that a number of mechanistic events are identical in mice and humans. Circulating biomarkers also seem to be useful in predicting the course of liver injury after APAP overdose in humans and hold promise for sig nificant clinical use in the near future.
Relevance for patients: This review focuses on the mechanisms behind APAP-induced hepatotoxicity and the relevance of these to the human pathophysiology. Current investigations on various biomarkers which may be useful in clinical management of APAP overdose patients are also discussed.
[1] Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 1364-1372.
[2] Reuben A, Tillman H, Fontana RJ, Davern T, McGuire B, Stravitz RT, Durkalski V, Larson AM, Liou I, Fix O, Schilsky M, McCash- land T, Hay JE, Murray N, Shaikh OS, Ganger D, Zaman A, Han SB, Chung RT, Smith A, Brown R, Crippin J, Harrison ME, Koch D, Munoz S, Reddy KR, Rossaro L, Satyanarayana R, Hassanein T, Hanje AJ, Olson J, Subramanian R, Karvellas C, Hameed B, Sherker AH, Robuck P, Lee WM. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med 2016; 164: 724-732.
[3] Lancaster EM, Hiatt JR, Zarrinpar A. Acetaminophen hepatotoxici ty: an updated review. Arch Toxicol 2015; 89: 193-199.
[4] Clark R, Fisher JE, Sketris IS, Johnston GM. Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescrip tion combinations: an observational study. BMC Clin Pharmacol 2012; 12: 11.
[5] Maes M, Vinken M, Jaeschke H. Experimental models of hepato toxicity related to acute liver failure. Toxicol Appl Pharmacol 2016; 290: 86-97.
[6] Jaeschke H, Xie Y, McGill MR. Acetaminophen-induced liver in jury: from animal models to humans. J Clin Transl Hepatol 2014; 2: 153-161.
[7] Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Aceta minophen-induced hepatic necrosis. IV. Protective role of glutathi one. J Pharm Exp Ther 1973; 187: 211-217.
[8] Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acety lcysteine. Lancet 1977; 2: 432-434.
[9] Peterson RG, Rumack BH. Treating acute acetaminophen poisoning with acetylcysteine. JAMA 1977; 237: 2406-2407.
[10] McGill MR, Jaeschke H. Metabolism and disposition of aceta minophen: recent advances in relation to hepatotoxicity and diag nosis. Pharm Res 2013; 30: 2174-2187.
[11] Zaher H, Buters JT, Ward JM, Bruno MK, Lucas AM, Stern ST, Cohen SD, Gonzalez FJ. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharma-col 1998; 152: 193-199.
[12] Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Seminars in liver disease 1990; 10: 267-278.
[13] Hinson JA, Monks TJ, Hong M, Highet RJ, Pohl LR. 3-(glu tathion-S-yl)acetaminophen: a biliary metabolite of acetaminophen. Drug Metab Dispos 1982; 10: 47-50.
[14] Chen C, Hennig GE, Manautou JE. Hepatobiliary excretion of ac etaminophen glutathione conjugate and its derivatives in transport-deficient (TR-) hyperbilirubinemic rats. Drug Metab Dispos 2003; 31: 798-804.
[15] McGill MR, Lebofsky M, Norris HR, Slawson MH, Bajt ML, Xie Y, Williams CD, Wilkins DG, Rollins DE, Jaeschke H. Plasma and liver acetaminophen-protein adduct levels in mice after acetamino phen treatment: dose-response, mechanisms, and clinical implica tions. Toxicol Appl Pharmacol 2013; 269: 240-249.
[16] Heard KJ, Green JL, James LP, Judge BS, Zolot L, Rhyee S, Dart RC. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose. BMC Gastroenterol 2011; 11: 20.
[17] Ni HM, McGill MR, Chao X, Du K, Williams JA, Xie Y, Jaeschke H, Ding WX. Removal of acetaminophen protein adducts by au tophagy protects against acetaminophen-induced liver injury in mice. J Hepatology 2016; 65: 354-362.
[18] Xie Y, McGill MR, Cook SF, Sharpe MR, Winefield RD, Wilkins DG, Rollins DE, Jaeschke H. Time course of acetamino phen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells. Xenobiotica 2015; 45: 921-929.
[19] Jaeschke H. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharm Exp Ther 1990; 255: 935-941.
[20] Du K, Williams CD, McGill MR, Jaeschke H. Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mito chondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol Appl Pharmacol 2014; 281: 58-66.
[21] Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakurakawa T, Kakazu Y, Ishikawa T, Robert M, Nishioka T, Tomita M. Differen tial metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem 2006; 281: 16768-16776.
[22] Kaur G, Leslie EM, Tillman H, Lee WM, Swanlund DP, Karvellas CJ, US Acute Liver Failure Study Group. Detection of ophthalmic acid in serum from acetaminophen-induced acute liver failure pa tients is more frequent in non-survivors. PLoS One 2015; 10: e0139299.
[23] McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins DE, Jaeschke H. HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 2011; 53: 974-982.
[24] Tirmenstein MA, Nelson SD. Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepato toxic regioisomer, 3'-hydroxyacetanilide, in mouse liver. J Biol Chem 1989; 264: 9814-9819.
[25] McGill MR, Williams CD, Xie Y, Ramachandran A, Jaeschke H. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol Appl Pharmacol 2012; 264: 387-394.
[26] Hu J, Ramshesh VK, McGill MR, Jaeschke H, Lemasters JJ. Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunc tion Associated with Transient c-Jun N-Terminal Kinase Activation in Mouse Liver. Toxicol Sci 2016; 150: 204-215.
[27] Baines CP. Role of the mitochondrion in programmed necrosis. Front Physiol 2010; 1: 156.
[28] Myers TG, Dietz EC, Anderson NL, Khairallah EA, Cohen SD, Nelson SD. A comparative study of mouse liver proteins arylated by reactive metabolites of acetaminophen and its nonhepatotoxic regioisomer, 3'-hydroxyacetanilide. Chem Res Toxicol 1995; 8: 403-413.
[29] Matthews AM, Hinson JA, Roberts DW, Pumford NR. Comparison of covalent binding of acetaminophen and the regioisomer 3'-hydr oxyacetanilide to mouse liver protein. Toxicol Lett 1997; 90: 77-82.
[30] Hadi M, Dragovic S, van Swelm R, Herpers B, van de Water B, Russel FG, Commandeur JN, Groothuis GM. AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver. Arch Toxicol 2013; 87: 155-165.
[31] Xie Y, McGill MR, Du K, Dorko K, Kumer SC, Schmitt TM, Ding WX, Jaeschke H. Mitochondrial protein adducts formation and mi tochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)- induced hepatotoxicity in primary human hepatocytes. Toxicol Appl Pharmacol 2015; 289: 213-222.
[32] Qiu Y, Benet LZ, Burlingame AL. Identification of the hepatic pro tein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spec trometry. J Biol Chem 1998; 273: 17940-17953.
[33] Andringa KK, Bajt ML, Jaeschke H, Bailey SM. Mitochondrial protein thiol modifications in acetaminophen hepatotoxicity: effect on HMG-CoA synthase. Toxicol Lett 2008; 177: 188-197.
[34] Bruderer R, Bernhardt OM, Gandhi T, Miladinovic SM, Cheng LY, Messner S, Ehrenberger T, Zanotelli V, Butscheid Y, Escher C, Vitek O, Rinner O, Reiter L. Extending the limits of quantitative proteome profiling with data-independent acquisition and applica tion to acetaminophen-treated three-dimensional liver microtissues. Mol Cell Proteomics 2015; 14: 1400-1410.
[35] Jaeschke H, Knight TR, Bajt ML. The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett 2003; 144: 279-288.
[36] Yan HM, Ramachandran A, Bajt ML, Lemasters JJ, Jaeschke H. The oxygen tension modulates acetaminophen-induced mitochon drial oxidant stress and cell injury in cultured hepatocytes. Toxicol Sci 2010; 117: 515-523.
[37] Meyers LL, Beierschmitt WP, Khairallah EA, Cohen SD. Aceta minophen-induced inhibition of hepatic mitochondrial respiration in mice. Toxicol Appl Pharmacol 1988; 93: 378-387.
[38] Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H. The impact of partial manganese superoxide dismutase (SOD2)- defi ciency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2011; 251: 226-233.
[39] Fujimoto K, Kumagai K, Ito K, Arakawa S, Ando Y, Oda S, Yamoto T, Manabe S. Sensitivity of liver injury in heterozygous Sod2 knockout mice treated with troglitazone or acetaminophen. Toxicol Pathol 2009; 37: 193-200.
[40] Radi R, Peluffo G, Alvarez MN, Naviliat M, Cayota A. Unraveling peroxynitrite formation in biological systems. Free Radic Biol Med 2001; 30: 463-488.
[41] Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, Jaeschke H. Peroxynitrite-induced mitochondrial and endonu clease- mediated nuclear DNA damage in acetaminophen hepato toxicity. J Pharmacol Exp Ther 2005; 315: 879-887.
[42] Saito C, Lemasters JJ, Jaeschke H. c-Jun N-terminal kinase modu lates oxidant stress and peroxynitrite formation independent of in ducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2010; 246: 8-17.
[43] Hinson JA, Bucci TJ, Irwin LK, Michael SL, Mayeux PR. Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice. Nitric Oxide 2002; 6: 160-167.
[44] Michael SL, Mayeux PR, Bucci TJ, Warbritton AR, Irwin LK, Pumford NR, Hinson JA. Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity. Nitric Oxide 2001; 5: 432-441.
[45] Villanueva C, Giulivi C. Subcellular and cellular locations of nitricoxide synthase isoforms as determinants of health and disease. Free Radic Biol Med 2010; 49: 307-316.
[46] Banerjee S, Melnyk SB, Krager KJ, Aykin-Burns N, Letzig LG, James LP, Hinson JA. The neuronal nitric oxide synthase inhibitor NANT blocks acetaminophen toxicity and protein nitration in freshly isolated hepatocytes. Free Radic Biol Med 2015; 89: 750-757.
[47] Agarwal R, Hennings L, Rafferty TM, Letzig LG, McCullough S, James LP, MacMillan-Crow LA, Hinson JA. Acetaminophen-induced hepatotoxicity and protein nitration in neuronal nitric-oxide synthase knockout mice. J Pharmocol Exp Ther 2012; 340: 134-142.
[48] Agarwal R, MacMillan-Crow LA, Rafferty TM, Saba H, Roberts DW, Fifer EK, James LP, Hinson JA. Acetaminophen-induced hepatotoxicity in mice occurs with inhibition of activity and nitration of mitochondrial manganese superoxide dismutase. J Pharmacol Exp Ther 2011; 337: 110-116.
[49] Knight TR, Ho YS, Farhood A, Jaeschke H. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmocol Exp Ther 2002; 303: 468-475.
[50] Bajt ML, Knight TR, Farhood A, Jaeschke H. Scavenging peroxynitrite with glutathione promotes regeneration and enhances survival during acetaminophen-induced liver injury in mice. J Pharmocol Exp Ther 2003; 307: 67-73.
[51] James LP, McCullough SS, Lamps LW, Hinson JA. Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation. Toxicol Sci 2003; 75: 458-467.
[52] Saito C, Zwingmann C, Jaeschke H. Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 2010; 51: 246-254.
[53] Du K, Farhood A, Jaeschke H. Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Arch Toxicol 2017; 91: 761-773.
[54] Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 2008; 283: 13565-13577.
[55] Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A, Sakamoto K, Ogura K, Noguchi T, Karin M, Ichijo H, Omata M. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterol 2008; 135: 1311-1321.
[56] Xie Y, Ramachandran A, Breckenridge DG, Liles JT, Lebofsky M, Farhood A, Jaeschke H. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury. Toxicol Appl Pharmacol 2015; 286: 1-9.
[57] Sharma M, Gadang V, Jaeschke A. Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity. Mol Pharmacol 2012; 82: 1001-1007.
[58] Lee HS, Hwang CY, Shin SY, Kwon KS, Cho KH. MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species. Sci Signal 2014; 7: ra52.
[59] Win S, Than TA, Han D, Petrovic LM, Kaplowitz N. c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice. J Biol Chem 2011; 286: 35071- 35078.
[60] Win S, Than TA, Min RW, Aghajan M, Kaplowitz N. c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src. Hepatology 2016; 63: 1987-2003.
[61] Cubero FJ, Zoubek ME, Hu W, Peng J, Zhao G, Nevzorova YA, AlMasaoudi M, Bechmann LP, Boekschoten MV, Muller M, Preisinger C, Gassler N, Canbay AE, Luedde T, Davis RJ, Liedtke C, Trautwein C. Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterol 2016; 150: 968-981.
[62] Bourdi M, Korrapati MC, Chakraborty M, Yee SB, Pohl LR. Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury. Biochem Biophys Res Commun 2008; 374: 6-10.
[63] Bourdi M, Davies JS, Pohl LR. Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. Chem Res Toxicol 2011; 24: 794-796.
[64] Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterol 2006; 131: 165-178.
[65] Henderson NC, Pollock KJ, Frew J, Mackinnon AC, Flavell RA, Davis RJ, Sethi T, Simpson KJ. Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure. Gut 2007; 56: 982-990.
[66] Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, Forster J, Jaeschke H. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol 2014; 279: 266-274.
[67] Bajt ML, Farhood A, Lemasters JJ, Jaeschke H. Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 2008; 324: 8-14.
[68] El-Hassan H, Anwar K, Macanas-Pirard P, Crabtree M, Chow SC, Johnson VL, Lee PC, Hinton RH, Price SC, Kass GE. Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases. Toxicol Appl Pharmacol 2003; 191: 118- 129.
[69] Karch J, Molkentin JD. Regulated necrotic cell death: the passive aggressive side of Bax and Bak. Circ Res 2015; 116: 1800-1809.
[70] Silva Ramos E, Larsson NG, Mourier A. Bioenergetic roles of mitochondrial fusion. Biochim Biophys Acta 2016; 1857: 1277-1283.
[71] Ishihara T, Kohno H, Ishihara N. Physiological roles of mitochondrial fission in cultured cells and mouse development. Ann N Y Acad Sci 2015; 1350: 77-81.
[72] Zhao J, Lendahl U, Nister M. Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates. Cell Mol Life Sci 2013; 70: 951-976.
[73] Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 2013; 58: 2099-2108.
[74] Dara L, Johnson H, Suda J, Win S, Gaarde W, Han D, Kaplowitz N. Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis. Hepatology 2015; 62: 1847-1857.
[75] Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, Youle RJ. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 2002; 159: 931-938.
[76] Wu S, Zhou F, Zhang Z, Xing D. Bax is essential for Drp1-mediated mitochondrial fission but not for mitochondrial outer membrane permeabilization caused by photodynamic therapy. J Cell Physiol 2011; 226: 530-541.
[77] Wang P, Wang P, Liu B, Zhao J, Pang Q, Agrawal SG, Jia L, Liu FT. Dynamin-related protein Drp1 is required for Bax translocation to mitochondria in response to irradiation-induced apoptosis. Oncotarget 2015; 6: 22598-22612.
[78] Montessuit S, Somasekharan SP, Terrones O, Lucken-ArdjomandeS, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basañez G, Meda P, Martinou JC. Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 2010; 142: 889-901.
[79] Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, Nunnari J. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 2008; 14: 193-204.
[80] Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX. Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 2012; 55: 222-232.
[81] Ni HM, Williams JA, Jaeschke H, Ding WX. Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen- induced necrosis in the liver. Redox Biol 2013; 1: 427-432.
[82] Williams JA, Ni HM, Haynes A, Manley S, Li Y, Jaeschke H, Ding WX. Chronic deletion and acute knockdown of Parkin have differential responses to acetaminophen-induced mitophagy and liver injury in mice. J Biol Chem 2015; 290: 10934-10946.
[83] Ding WX, Guo F, Ni HM, Bockus A, Manley S, Stolz DB, Eskelinen EL, Jaeschke H, Yin XM. Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J Biol Chem 2012; 287: 42379- 42388.
[84] Ni HM, Boggess N, McGill MR, Lebofsky M, Borude P, Apte U, Jaeschke H, Ding WX. Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. Toxicol Sci 2012; 127: 438-450.
[85] Ramachandran A, Lebofsky M, Yan HM, Weinman SA, Jaeschke H. Hepatitis C virus structural proteins can exacerbate or ameliorate acetaminophen-induced liver injury in mice. Arch Toxicol 2015; 89: 773-783.
[86] Nagy G, Kardon T, Wunderlich L, Szarka A, Kiss A, Schaff Z, Bánhegyi G, Mandl J. Acetaminophen induces ER dependent signaling in mouse liver. Arch Biochem Biophys 2007; 459: 273-279.
[87] Uzi D, Barda L, Scaiewicz V, Mills M, Mueller T, GonzalezRodriguez A, Valverde AM, Iwawaki T, Nahmias Y, Xavier R, Chung RT, Tirosh B, Shibolet O. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 2013; 59: 495- 503.
[88] Foufelle F, Fromenty B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol Res Perspect 2016; 4: e00211.
[89] Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim. Biophys. Acta 1995; 1241: 139-176.
[90] Karch J, Kwong JQ, Burr AR, Sargent MA, Elrod JW, Peixoto PM, Martinez-Caballero S, Osinska H, Cheng EH, Robbins J, Kinnally KW, Molkentin JD. Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice. eLife 2013; 2: e00772.
[91] Karch J, Molkentin JD. Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 2014; 111: 10396-10397.
[92] Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005; 434: 658-662
[93] Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA, Licznerski P, Li H, Nabili P, Hockensmith K, Graham M, Porter GA Jr, Jonas EA. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 2014; 111: 10580-10585.
[94] Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 2004; 40: 1170-1179.
[95] Masubuchi Y, Suda C, Horie T. Involvement of mitochondrial per-meability transition in acetaminophen-induced liver injury in mice. J Hepatol 2005; 42: 110-116.
[96] Ramachandran A, Lebofsky M, Baines CP, Lemasters JJ, Jaeschke H. Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury. Free Radic Res 2011; 45: 156-164.
[97] Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson JA. Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Therap 2005; 312: 509-516.
[98] LoGuidice A, Boelsterli UA. Acetaminophen overdose-induced liver injury in mice is mediated by peroxynitrite independently of the cyclophilin D-regulated permeability transition. Hepatology 2011; 54: 969-978.
[99] Brenner C, Moulin M. Physiological roles of the permeability transition pore. Circ Res 2012; 111: 1237-1247.
[100] Kwong JQ, Molkentin JD. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab 2015; 21: 206-214.
[101] Mnatsakanyan N, Beutner G, Porter GA, Alavian KN, Jonas EA. Physiological roles of the mitochondrial permeability transition pore. J Bioenerg Biomembr 2017; in press
[102] Kon K, Kim JS, Uchiyama A, Jaeschke H, Lemasters JJ. Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes. Toxicol Sci 2010; 117: 101-108.
[103] Hu J, Kholmukhamedov A, Lindsey CC, Beeson CC, Jaeschke H, Lemasters JJ. Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury: Protection by starch-desferal and minocycline. Free Radic Biol Med 2016; 97: 418-426.
[104] Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 2010; 11: 621-632.
[105] Munoz-Pinedo C, Guio-Carrion A, Goldstein JC, Fitzgerald P, Newmeyer DD, Green DR. Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration. Proc Natl Acad Sci U S A 2006; 103: 11573-11578.
[106] Arnoult D, Gaume B, Karbowski M, Sharpe JC, Cecconi F, Youle RJ. Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. EMBO J 2003; 22: 4385-4399.
[107]Bajt ML, Cover C, Lemasters JJ, Jaeschke H. Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci 2006; 94: 217-225.
[108] Norberg E, Orrenius S, Zhivotovsky B. Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochem Biophys Res Commun 2010; 396: 95-100.
[109] Widlak P, Garrard WT. Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G. J Cell Biochem 2005; 94: 1078-87.
[110]Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001; 61: 1659-1665
[111]Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA. AIF- mediated programmed necrosis: a highly regulated way to die. Cell Cycle 2007; 6: 2612-2619.
[112]Bajt ML, Ramachandran A, Yan HM, Lebofsky M, Farhood A, Lemasters JJ, Jaeschke H. Apoptosis-inducing factor modulates mitochondrial oxidant stress in acetaminophen hepatotoxicity. Toxicol Sci 2011; 122: 598-605.
[113] Knight TR, Jaeschke H. Acetaminophen-induced inhibition of Fasreceptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion. Toxicol Appl Pharmacol 2002; 181: 133-141.
[114] Lawson JA, Fisher MA, Simmons CA, Farhood A, Jaeschke H. Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice. Toxicol Appl Pharmacol 1999; 156: 179-86.
[115]Jaeschke H, Cover C, Bajt ML. Role of caspases in acetaminophen-induced liver injury. Life Sci 2006; 78: 1670-1676.
[116]Jacob M, Mannherz HG, Napirei M. Chromatin breakdown by deoxyribonuclease1 promotes acetaminophen-induced liver necrosis: an ultrastructural and histochemical study on male CD-1 mice. Histochem Cell Biol 2007; 128: 19-33.
[117]Jaeschke H, Gujral JS, Bajt ML. Apoptosis and necrosis in liver disease. Liver Int 2004; 24: 85-89.
[118] Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci 2002; 67: 322-328.
[119] Williams CD, Farhood A, Jaeschke H. Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. Toxicol Appl Pharmacol 2010; 247: 169-178.
[120] Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010; 11: 700-714.
[121] Zhang J, Yang Y, He W, Sun L. Necrosome core machinery: MLKL. Cell Mol Life Sci 2016; 73: 2153-2163.
[122] Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T. The role of the kinases RIP1 and RIP3 in TNF- induced necrosis. Sci Signal 2010; 3: re4.
[123] Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325: 332-336.
[124] Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012; 148: 213-227.
[125] Deutsch M, Graffeo CS, Rokosh R, Pansari M, Ochi A, Levie EM, Van Heerden E1, Tippens DM1, Greco S1, Barilla R1, Tomkötter L, Zambirinis CP, Avanzi N, Gulati R, Pachter HL, Torres-Hernandez A, Eisenthal A, Daley D, Miller G. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis 2015; 6: e1759.
[126]Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 2013; 57: 1773-1783.
[127] Gautheron J, Vucur M, Reisinger F, Cardenas DV, Roderburg C, Koppe C, Kreggenwinkel K, Schneider AT, Bartneck M, Neumann UP, Canbay A, Reeves HL, Luedde M, Tacke F, Trautwein C, Heikenwalder M, Luedde T. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol Med 2014; 6: 1062-1074.
[128] McGill MR, Du K, Xie Y, Bajt ML, Ding WX, Jaeschke H. The role of the c-Jun N-terminal kinases 1/2 and receptor-interacting protein kinase 3 in furosemide-induced liver injury. Xenobiotica 2015; 45: 442-449.
[129] Li JX, Feng JM, Wang Y, Li XH, Chen XX, Su Y, Shen YY, Chen Y, Xiong B, Yang CH, Ding J, Miao ZH. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell Death Dis 2014; 5: e1278.
[130] Yang X, Chao X, Wang ZT, Ding WX. The end of RIPK1-RIPK3- MLKL-mediated necroptosis in acetaminophen-induced hepatotoxicity? Hepatology 2016; 64: 311-312
[131] Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW, Gough PJ, Sehon CA, Marquis RW, Bertin J, Mocarski ES. Toll-like receptor3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem 2013; 288: 31268-31279.
[132] Gunther C, He GW, Kremer AE, Murphy JM, Petrie EJ, Amann K, Vandenabeele P, Linkermann A, Poremba C, Schleicher U, Dewitz C, Krautwald S, Neurath MF, Becker C, Wirtz S. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. J Clin Invest 2016; 126: 4346-4360.
[133] Gardner CR, Laskin JD, Dambach DM, Chiu H, Durham SK, Zhou P, Bruno M, Gerecke DR, Gordon MK, Laskin DL. Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1. Potential role of inflammatory mediators. Toxicol Appl Pharmacol 2003; 192: 119-130.
[134]Boess F, Bopst M, Althaus R, Polsky S, Cohen SD, Eugster HP, Boelsterli UA. Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-alpha gene knockout mice. Hepatology 1998; 27: 1021-1029.
[135] Zhang T, Zhang Y, Cui M, Jin L, Wang Y, Lv F, Liu Y, Zheng W, Shang H, Zhang J, Zhang M, Wu H, Guo J, Zhang X, Hu X, Cao CM, Xiao RP. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat Med 2016; 22: 175-182.
[136] Zhang YF, He W, Zhang C, Liu XJ, Lu Y, Wang H, Zhang ZH, Chen X, Xu DX. Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice. Toxicol Lett 2014; 225: 445-453.
[137] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060-1072.
[138] Lorincz T, Jemnitz K, Kardon T, Mandl J, Szarka A. Ferroptosis is involved in acetaminophen induced cell death. Pathol Oncol Res 2015; 21: 1115-1121.
[139] Woolbright BL, Jaeschke H. Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol 2017; in press.
[140]Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 2009; 119: 305-314.
[141] Hoque R, Sohail MA, Salhanick S, Malik AF, Ghani A, Robson SC, Mehal WZ. P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am J Physiol Gastrointest Liver Physiol 2012; 302: G1171-1179.
[142] Xie Y, Williams CD, McGill MR, Lebofsky M, Ramachandran A, Jaeschke H. Purinergic receptor antagonist A438079 protects against acetaminophen-induced liver injury by inhibiting p450 isoenzymes, not by inflammasome activation. Toxicol Sci 2013; 131: 325-335.
[143]Jaeschke H, Williams CD, Ramachandran A, Bajt ML. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 2012; 32: 8-20.
[144] Woolbright BL, Jaeschke H. The impact of sterile inflammation in Acute Liver Injury. J Clin Transl Res 2017, in press.
[145] Vinken M. Gap junctions and non-neoplastic liver disease. J Hepatol 2012; 57: 655-662.
[146] Patel SJ, Milwid JM, King KR, Bohr S, Iracheta-Vellve A, Li M, Vitalo A, Parekkadan B, Jindal R, Yarmush ML. Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. Nat Biotechnol 2012; 30: 179-183.
[147] Du K, Williams CD, McGill MR, Xie Y, Farhood A, Vinken M, Jaeschke H. The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by in-hibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation. Toxicol Appl Pharmacol 2013; 273: 484-491.
[148] Maes M, McGill MR, da Silva TC, Lebofsky M, Maria Monteiro de Araujo C, Tiburcio T, Veloso Alves Pereira I, Willebrords J, Crespo Yanguas S, Farhood A, Zaidan Dagli ML, Jaeschke H, Cogliati B, Vinken M.Connexin32: a mediator of acetaminophen-induced liver injury? Toxicol Mech Methods 2016; 26: 88-96.
[149] Maes M, McGill MR, da Silva TC, Abels C, Lebofsky M, Maria Monteiro de Araujo C, Tiburcio T, Veloso Alves Pereira I, Willebrords J, Crespo Yanguas S, Farhood A, Beschin A, Van Ginderachter JA, Zaidan Dagli ML, Jaeschke H, Cogliati B, Vinken M. Involvement of connexin43 in acetaminophen-induced liver injury. Biochim Biophys Acta 2016; 1862: 1111-1121.
[150] Maes M, McGill MR, da Silva TC, Abels C, Lebofsky M, Weemhoff JL, Tiburcio T, Veloso Alves Pereira I, Willebrords J, Crespo Yanguas S, Farhood A, Beschin A, Van Ginderachter JA, Penuela S, Jaeschke H, Cogliati B, Vinken M. Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity. Arch Toxicol 2017; in press.
[151] Maes M, Vinken M. Connexin-based signaling and drug-induced hepatotoxicity. J Clin Transl Res 2017; in press.
[152]Rodriguez-Antona C, Donato MT, Boobis A, Edwards RJ, Watts PS, Castell JV, Gómez-Lechón MJ. Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: molecular mechanisms that determine lower expression in cultured cells. Xenobiotica 2002; 32: 505-520
[153] Davern TJ, 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM; Acute Liver Failure Study Group. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterol 2006; 130: 687-694.
[154] Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing. Br J Clin Pharmacol 2016; 81: 562-568.
[155] McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen- induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012; 122: 1574-1583.
[156] McGill MR, Staggs VS, Sharpe MR, Lee WM, Jaeschke H, Acute Liver Failure Study Group. Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome. Hepatology 2014; 60: 1336-1345.
[157] Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR, Sharpe MR, Craig DG, Simpson KJ, Jaeschke H, Park BK. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkersfor mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol 2012; 56: 1070-1079.
[158] Starkey Lewis PJ, Dear J, Platt V, Simpson KJ, Craig DG, Antoine DJ, French NS, Dhaun N, Webb DJ, Costello EM, Neoptolemos JP, Moggs J, Goldring CE, Park BK. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 2011; 54: 1767-1776.
[159] Yang R, Zhang S, Cotoia A, Oksala N, Zhu S, Tenhunen J. High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity. BMC Gastroenterol 2012; 12: 45.
[160] Yang R, Zou X, Tenhunen J, Zhu S, Kajander H, Koskinen ML, Tonnessen TI. HMGB1 neutralization is associated with bacterial translocation during acetaminophen hepatotoxicity. BMC Gastroenterol 2014; 14: 66.
[161] Lundback P, Lea JD, Sowinska A, Ottosson L, Furst CM, Steen J, Aulin C, Clarke JI, Kipar A, Klevenvall L, Yang H, Palmblad K, Park BK, Tracey KJ, Blom AM, Andersson U, Antoine DJ, Erlandsson Harris H. A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice. Hepatology 2016; 64: 1699-1710.
[162] McGill MR, Jaeschke H. Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients. Expert Opin Drug Metab Toxicol 2014; 10: 1005-1117.
[163] Woolbright BL, McGill MR, Staggs VS, Winefield RD, Gholami P, Olyaee M, Sharpe MR, Curry SC, Lee WM, Jaeschke H; Acute Liver Failure Study Group. Glycodeoxycholic acid levels as prognostic biomarker in acetaminophen-induced acute liver failure patients. Toxicol Sci 2014; 142: 436-444.
[164] Antoine DJ, Dear JW, Lewis PS, Platt V, Coyle J, Masson M, Thanacoody RH, Gray AJ, Webb DJ, Moggs JG, Bateman DN, Goldring CE, Park BK. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 2013; 58: 777-787.
[165] McGill MR, Cao M, Svetlov A, Sharpe MR, Williams CD, Curry SC, Farhood A, Jaeschke H, Svetlov SI. Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans. Biomarkers 2014; 19: 222-230.
[166] Ward J, Kanchagar C, Veksler-Lublinsky I, Lee RC, McGill MR, Jaeschke H, Curry SC, Ambros VR. Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci U S A 2014; 111: 12169- 12174.
[167] Ma DKG, Stolte C, Krycer JR, James DE, O’Donoghue SI. SnapShot: Insulin/IGF1 Signaling. Cell 2015; 161: 948.