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Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity

  • Organ Toxicity and Mechanisms
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Abstract

We previously reported that delayed treatment with Mito-tempo (MT), a mitochondria-targeted superoxide dismutase mimetic, protects against the early phase of acetaminophen (APAP) hepatotoxicity by inhibiting peroxynitrite formation. However, whether this protection is sustained to the late phase of toxicity is unknown. To investigate the late protection, C57Bl/6J mice were treated with 300 mg/kg APAP followed by 20 mg/kg MT 1.5 h or 3 h later. We found that both MT treatments protected against the late phase of APAP hepatotoxicity at 12 and 24 h. Surprisingly, MT-treated mice demonstrated a significant increase in apoptotic hepatocytes, while the necrotic phenotype was observed almost exclusively in mice treated with APAP alone. In addition, there was a significant increase in caspase-3 activity and cleavage in the livers of MT-treated mice. Immunostaining for active caspase-3 revealed that the positively stained hepatocytes were exclusively in centrilobular areas. Treatment with the pan-caspase inhibitor ZVD-fmk (10 mg/kg) 2 h post-APAP neutralized this caspase activation and provided additional protection against APAP hepatotoxicity. Treatment with N-acetylcysteine, the current standard of care for APAP poisoning, protected but did not induce this apoptotic phenotype. Mechanistically, MT treatment inhibited APAP-induced RIP3 kinase expression, and RIP3-deficient mice showed caspase activation and apoptotic morphology in hepatocytes analogous to MT treatment. These data suggest that while necrosis is the primary cause of cell death after APAP hepatotoxicity, treatment with the antioxidant MT may switch the mode of cell death to secondary apoptosis in some cells. Modulation of mitochondrial oxidative stress and RIP3 kinase expression play critical roles in this switch.

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Abbreviations

ALT:

Alanine aminotransferase

APAP:

Acetaminophen

CYP:

Cytochrome P450

Gal:

d-Galactosamine

GSH:

Glutathione

GSSG:

Glutathione disulfide

ET:

Endotoxin (lipopolysaccharide)

MPT:

Mitochondrial permeability transition

MT:

Mito-Tempo

NAC:

N-Acetylcysteine

NAPQI:

N-Acetyl-p-benzoquinone imine

ROS:

Reactive oxygen species

RFU:

Relative fluorescence units

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

References

  • Adams ML, Pierce RH, Vail ME, White CC, Tonge RP, Kavanagh TJ, Fausto N, Nelson SD, Bruschi SA (2001) Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2. Mol Pharmacol 60:907–915

    Article  CAS  PubMed  Google Scholar 

  • Antoine DJ, Williams DP, Kipar A, Jenkins RE, Regan SL, Sathish JG, Kitteringham NR, Park BK (2009) High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci 112:521–531

    Article  CAS  PubMed  Google Scholar 

  • Antoine DJ, Williams DP, Kipar A, Laverty H, Park BK (2010) Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. Mol Med 16:479–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR, Sharpe MR, Craig DG, Simpson KJ, Jaeschke H, Park BK (2012) Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol 56:1070–1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 (2013) Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 58:777–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bajt ML, Lawson JA, Vonderfecht SL, Gujral JS, Jaeschke H (2000) Protection against Fas receptor-mediated apoptosis in hepatocytes and nonparenchymal cells by a caspase-8 inhibitor in vivo: evidence for a postmitochondrial processing of caspase-8. Toxicol Sci 58:109–117

    Article  CAS  PubMed  Google Scholar 

  • Bajt ML, Knight TR, Lemasters JJ, Jaeschke H (2004) Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetylcysteine. Toxicol Sci 80:343–349

    Article  CAS  PubMed  Google Scholar 

  • Bajt ML, Farhood A, Lemasters JJ, Jaeschke H (2008) Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 324:8–14

    Article  CAS  PubMed  Google Scholar 

  • Borutaite V, Brown GC (2001) Caspases are reversibly inactivated by hydrogen peroxide. FEBS Lett 500:114–118

    Article  CAS  PubMed  Google Scholar 

  • Budnitz DS, Lovegrove MC, Crosby AE (2011) Emergency department visits for overdoses of acetaminophen-containing products. Am J Prev Med 40:585–592

    Article  PubMed  Google Scholar 

  • Corcoran GB, Racz WJ, Smith CV, Mitchell JR (1985) Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice. J Pharmacol Exp Ther 232:864–872

    CAS  PubMed  Google Scholar 

  • Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, Jaeschke H (2005) Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 315:879–887

    Article  CAS  PubMed  Google Scholar 

  • Dara L, Johnson H, Suda J, Win S, Gaarde W, Han D, Kaplowitz N (2015) Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis. Hepatology 62:1847–1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dear JW, Morrison E, Henriksen D, Nasstrom J (2017) Calmangafodipir is a new treatment for late stage liver toxicity after acetaminophen overdose. Hepatology 66(Supplement 1):4A–5A

    Google Scholar 

  • Deutsch M, Graffeo CS, Rokosh R, Deutsch M, Graffeo CS, Rokosh R, Pansari M, Ochi A, Levie EM, Van Heerden E, Tippens DM, Greco S, Barilla R, Tomkötter L (2015) Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis 6:e1759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du K, Ramachandran A, Jaeschke H (2016a) Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol 10:148–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du K, Ramachandran A, Weemhoff JL, Chavan H, Xie Y, Krishnamurthy P, Jaeschke H (2016b) Editor’s highlight: metformin protects against acetaminophen hepatotoxicity by attenuation of mitochondrial oxidant stress and dysfunction. Toxicol Sci 154:214–226

  • Du K, Farhood A, Jaeschke H (2017) Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Arch Toxicol 91:761–773

    Article  CAS  PubMed  Google Scholar 

  • Eguchi A, Wree A, Feldstein AE (2014) Biomarkers of liver cell death. J Hepatol 60:1063–1074

    Article  CAS  PubMed  Google Scholar 

  • El-Hassan H, Anwar K, Macanas-Pirard P, Crabtree M, Chow SC, Johnson VL, Lee PC, Hinton RH, Price SC, Kass GE (2003) Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases. Toxicol Appl Pharmacol 191:118–129

    Article  CAS  PubMed  Google Scholar 

  • Golbidi S, Botta A, Gottfred S, Nusrat A, Laher I, Ghosh S (2014) Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise. Br J Pharmacol 171:5345–5360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R (1995) In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21:1465–1468

    CAS  PubMed  Google Scholar 

  • Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H (2002) Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci 67:322–328

    Article  CAS  PubMed  Google Scholar 

  • Hampton MB, Orrenius S (1997) Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett 414:552–556

    Article  CAS  PubMed  Google Scholar 

  • Horng CT, Liu ZH, Huang YT, Lee HJ, Wang CJ (2017) Extract from Mulberry (Morus australis) leaf decelerate acetaminophen induced hepatic inflammation involving downregulation of myeloid differentiation factor 88 (MyD88) signals. J Food Drug Anal 25:862–871

    Article  CAS  PubMed  Google Scholar 

  • Hu JN, Liu Z, Wang Z, Li XD, Zhang LX, Li W, Wang YP (2017) Ameliorative effects and possible molecular mechanism of action of black ginseng (Panax ginseng) on acetaminophen-mediated liver injury. Molecules 22(4):E664

    Article  CAS  PubMed  Google Scholar 

  • Jacob M, Mannherz HG, Napirei M (2007) Chromatin breakdown by deoxyribonuclease1 promotes acetaminophen-induced liver necrosis: an ultrastructural and histochemical study on male CD-1 mice. Histochem Cell Biol 128:19–33

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H (1990) Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther 255:935–941

    CAS  PubMed  Google Scholar 

  • Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89:31–41

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H, Lemasters JJ (2003) Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 125:1246–1257

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H, Fisher MA, Lawson JA, Simmons CA, Farhood A, Jones DA (1998) Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol 160:3480–3486

    CAS  PubMed  Google Scholar 

  • Jaeschke H, Gujral JS, Bajt ML (2004) Apoptosis and necrosis in liver disease. Liver Int 24:85–89

    Article  PubMed  Google Scholar 

  • Jaeschke H, Cover C, Bajt ML (2006) Role of caspases in acetaminophen-induced liver injury. Life Sci 78:1670–1676

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H, Williams CD, Farhood A (2011) No evidence for caspase-dependent apoptosis in acetaminophen hepatotoxicity. Hepatology 53:718–719

    Article  PubMed  Google Scholar 

  • Jaeschke H, Williams CD, Ramachandran A, Bajt ML (2012) Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 32:8–20

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H, Duan L, Akakpo JY, Farhood A, Ramachandran A (2018) The role of apoptosis in acetaminophen hepatotoxicity. Food Chem Toxicol 118:709–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • James LP, McCullough SS, Lamps LW, Hinson JA (2003) Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation. Toxicol Sci 75:458–467

    Article  CAS  PubMed  Google Scholar 

  • Knight TR, Jaeschke H (2002) Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion. Toxicol Appl Pharmacol 181:133–141

    Article  CAS  PubMed  Google Scholar 

  • Knight TR, Ho YS, Farhood A, Jaeschke H (2002) Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmacol Exp Ther 303:468–475

    Article  CAS  PubMed  Google Scholar 

  • Kon K, Kim JS, Jaeschke H, Lemasters JJ (2004) Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 40:1170–1179

    Article  CAS  PubMed  Google Scholar 

  • Lawson JA, Fisher MA, Simmons CA, Farhood A, Jaeschke H (1999) Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice. Toxicol Appl Pharmacol 156:179–186

    Article  CAS  PubMed  Google Scholar 

  • Lawson JA, Farhood A, Hopper RD, Bajt ML, Jaeschke H (2000) The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci 54:509–516

    Article  CAS  PubMed  Google Scholar 

  • Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150:339–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li JX, Feng JM, Wang Y, Li XH, Chen XX, Su Y, Shen YY, Chen Y, Xiong B, Yang CH, Ding J (2014) The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell Death Dis 5:e1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LoGuidice A, Boelsterli UA (2011) Acetaminophen overdose-induced liver injury in mice is mediated by peroxynitrite independently of the cyclophilin D-regulated permeability transition. Hepatology 54:969–978

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Zhang C, Chen YH, Wang H, Zhang ZH, Chen X, Xu DX (2017) Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury. Sci Rep 7:42736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manthripragada AD, Zhou EH, Budnitz DS, Lovegrove MC, Willy ME (2011) Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States. Pharmacoepidemiol Drug Saf 20:819–826

    Article  PubMed  Google Scholar 

  • Masubuchi Y, Suda C, Horie T (2005) Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 42:110–116

    Article  CAS  Google Scholar 

  • McGill MR, Jaeschke H (2013) Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res 30:2174–2187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGill MR, Jaeschke H (2014) Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients. Expert Opin Drug Metab Toxicol 10:1005–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGill MR, Jaeschke H (2015) A direct comparison of methods used to measure oxidized glutathione in biological samples: 2-vinylpyridine and N-ethylmaleimide. Toxicol Mech Methods 25:589–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins DE, Jaeschke H (2011) HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 53:974–982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Investig 122:1574–1583

    Article  CAS  Google Scholar 

  • Meyers LL, Beierschmitt WP, Khairallah EA, Cohen SD (1988) Acetaminophen-induced inhibition of hepatic mitochondrial respiration in mice. Toxicol Appl Pharmacol 93:378–387

    Article  CAS  PubMed  Google Scholar 

  • Mignon A, Rouquet N, Fabre M, Martin S, Pagès JC, Dhainaut JF, Kahn A, Briand P, Joulin V (1999) LPS challenge in d-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. Am J Respir Crit Care Med 159(4 Pt 1):1308–1315

    Article  CAS  PubMed  Google Scholar 

  • Nelson SD (1990) Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 10:267–278

    Article  CAS  PubMed  Google Scholar 

  • Possamai LA, McPhail MJ, Quaglia A, Zingarelli V, Abeles RD, Tidswell R, Puthucheary Z, Rawal J, Karvellas CJ, Leslie EM, Hughes RD, Ma Y, Jassem W, Shawcross DL, Bernal W, Dharwan A, Heaton ND, Thursz M, Wendon JA, Mitry RR, Antoniades CG (2013) Character and temporal evolution of apoptosis in acetaminophen-induced acute liver failure. Crit Care Med 41:2543–2550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramachandran A, Lebofsky M, Baines CP, Lemasters JJ, Jaeschke H (2011a) Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury. Free Radic Res 45:156–164

    Article  CAS  PubMed  Google Scholar 

  • Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H (2011b) The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 251:226–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H (2013) Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 58:2099–2108

    Article  CAS  PubMed  Google Scholar 

  • Ray SD, Sorge CL, Raucy JL, Corcoran GB (1990) Early loss of large genomic DNA in vivo with accumulation of Ca2+ in the nucleus during acetaminophen-induced liver injury. Toxicol Appl Pharmacol 106:346–351

    Article  CAS  PubMed  Google Scholar 

  • Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE (2013) Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773–1783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito C, Zwingmann C, Jaeschke H (2010) Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51:246–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schüngel S, Buitrago-Molina LE, Nalapareddy P, Lebofsky M, Manns MP, Jaeschke H, Gross A, Vogel A (2009) The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers. Hepatology 50:1558–1566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sen CK, Roy S (2001) Redox control of caspases. Environ Toxicol Pharmacol 10:215–220

    Article  CAS  PubMed  Google Scholar 

  • Skulachev VP (2006) Bioenergetic aspects of apoptosis, necrosis and mitoptosis. Apoptosis 11:473–485

    Article  CAS  PubMed  Google Scholar 

  • Thulin P, Nordahl G, Gry M, Yimer G, Aklillu E, Makonnen E, Aderaye G, Lindquist L, Mattsson CM, Ekblom B, Antoine DJ, Park BK, Linder S, Harrill AH, Watkins PB, Glinghammar B, Schuppe-Koistinen I (2014) Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int 34(3):367–378

    Article  CAS  PubMed  Google Scholar 

  • Tirmenstein MA, Nelson SD (1989) Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J Biol Chem 264:9814–9819

    CAS  PubMed  Google Scholar 

  • Wang X, Liu J, Zhang X, Zhao S, Zou K, Xie J, Wang X, Liu C, Wang J, Wang Y (2018) Seabuckthorn berry polysaccharide extracts protect against acetaminophen induced hepatotoxicity in mice via activating the Nrf-2/HO-1-SOD-2 signaling pathway. Phytomedicine 38:90–97

    Article  CAS  PubMed  Google Scholar 

  • Weemhoff JL, Woolbright BL, Jenkins RE, McGill MR, Sharpe MR, Olson JC, Antoine DJ, Curry SC, Jaeschke H (2017) Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis. Liver Int 37(3):377–384

    Article  CAS  PubMed  Google Scholar 

  • Williams CD, Farhood A, Jaeschke H (2010) Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. Toxicol Appl Pharmacol 247(3):169–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams CD, Koerner MR, Lampe JN, Farhood A, Jaeschke H (2011) Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation. Toxicol Appl Pharmacol 257:449–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolbright BL, Jaeschke H (2017) Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol 66:836–848

    Article  CAS  PubMed  Google Scholar 

  • Woolbright BL, Bridges BW, Dunn W, Olson JC, Weinman SA, Jaeschke H (2017) Cell death and prognosis of mortality in alcoholic hepatitis patients using plasma keratin-18. Gene Expr 17(4):301–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, Forster J, Jaeschke H (2014) Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol 279:266–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Y, McGill MR, Du K, Dorko K, Kumer SC, Schmitt TM, Ding WX, Jaeschke H (2015) Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes. Toxicol Appl Pharmacol 289:213–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332–336

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Song Q, Han X, Zhang Y, Zhang Y, Zhang X, Chu X, Zhang F, Chu L (2017) Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid. Int Immunopharmacol 47:95–105

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This investigation was supported in part by the National Institutes of Health grant R01 DK102142 and by grants from the National Institute of General Medical Sciences (P20 GM103549 and P30 GM118247) from the National Institutes of Health. Additional support came as an award from the Biomedical Research Training Program (BRTP) from the University of Kansas Medical Center (to K.D.).

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  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA

    Kuo Du, Anup Ramachandran, James L. Weemhoff, Benjamin L. Woolbright, Andrew H. Jaeschke, Xiaojuan Chao, Wen-Xing Ding & Hartmut Jaeschke

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  1. Kuo Du
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  2. Anup Ramachandran
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  3. James L. Weemhoff
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Correspondence to Hartmut Jaeschke.

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Du, K., Ramachandran, A., Weemhoff, J.L. et al. Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity. Arch Toxicol 93, 163–178 (2019). https://doi.org/10.1007/s00204-018-2331-8

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