CLC number:
On-line Access: 2024-08-27
Received: 2023-10-17
Revision Accepted: 2024-05-08
Crosschecked: 2022-04-19
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Citations: Bibtex RefMan EndNote GB/T7714
Xiaopeng CAI, Huiqiang CAI, Jing WANG, Qin YANG, Jun GUAN, Jingwen DENG, Zhi CHEN. Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options[J]. Journal of Zhejiang University Science B, 2022, 23(4): 265-285.
@article{title="Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options",
author="Xiaopeng CAI, Huiqiang CAI, Jing WANG, Qin YANG, Jun GUAN, Jingwen DENG, Zhi CHEN",
journal="Journal of Zhejiang University Science B",
volume="23",
number="4",
pages="265-285",
year="2022",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2100977"
}
%0 Journal Article
%T Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options
%A Xiaopeng CAI
%A Huiqiang CAI
%A Jing WANG
%A Qin YANG
%A Jun GUAN
%A Jingwen DENG
%A Zhi CHEN
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 4
%P 265-285
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2100977
TY - JOUR
T1 - Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options
A1 - Xiaopeng CAI
A1 - Huiqiang CAI
A1 - Jing WANG
A1 - Qin YANG
A1 - Jun GUAN
A1 - Jingwen DENG
A1 - Zhi CHEN
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 4
SP - 265
EP - 285
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100977
Abstract: acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.
[1]AkakpoJY, RamachandranA, KandelSE, et al., 2018. 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Hum Exp Toxicol, 37(12):1310-1322.
[2]AkakpoJY, RamachandranA, JaeschkeH, 2020. Novel strat
[3]egies for the treatment of acetaminophen hepatotoxicity. Expert Opin Drug Metab Toxicol, 16(11):1039-1050.
[4]AntoniadesCG, QuagliaA, TaamsLS, et al., 2012. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatology, 56(2):735-746.
[5]ApteU, SinghS, ZengG, et al., 2009. Beta-catenin activation promotes liver regeneration after acetaminophen-induced injury. Am J Pathol, 175(3):1056-1065.
[6]Barbier-TorresL, IruzubietaP, Fernández-RamosD, et al., 2017. The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury. Nat Commun, 8:2068.
[7]BerryPA, AntoniadesCG, HussainMJ, et al., 2010. Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis. Liver Int, 30(5):733-740.
[8]BhushanB, ApteU, 2019. Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities. Am J Pathol, 189(4):719-729.
[9]BhushanB, WaleskyC, ManleyM, et al., 2014. Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model. Am J Pathol, 184(11):3013-3025.
[10]BhushanB, ChavanH, BorudeP, et al., 2017a. Dual role of epidermal growth factor receptor in liver injury and regeneration after acetaminophen overdose in mice. Toxicol Sci, 155(2):363-378.
[11]BhushanB, PoudelS, ManleyMW, et al., 2017b. Inhibition of glycogen synthase kinase 3 accelerated liver regeneration after acetaminophen-induced hepatotoxicity in mice. Am J Pathol, 187(3):543-552.
[12]BilzerM, RoggelF, GerbesAL, 2006. Role of kupffer cells in host defense and liver disease. Liver Int, 26(10):1175-1186.
[13]BirdTG, MüllerM, BoulterL, et al., 2018. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med, 10(454):eaan1230.
[14]BlazkaME, WilmerJL, HolladaySD, et al., 1995. Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol, 133(1):43-52.
[15]BoessF, BopstM, AlthausR, et al., 1998. Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-αgene knockout mice. Hepatology, 27(4):1021-1029.
[16]BonaldiT, TalamoF, ScaffidiP, et al., 2003. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J, 22(20):5551-5560.
[17]BorudeP, BhushanB, GunewardenaS, et al., 2018. Pleiotropic role of p53 in injury and liver regeneration after acetaminophen overdose. Am J Pathol, 188(6):1406-1418.
[18]BourdiM, MasubuchiY, ReillyTP, et al., 2002. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology, 35(2):289-298.
[19]BrudererR, BernhardtOM, GandhiT, et al., 2015. Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol Cell Proteomics, 14(5):1400-1410.
[20]CaiCC, HuangH, WhelanS, et al., 2014. Benzyl alcohol attenuates acetaminophen-induced acute liver injury in a Toll-like receptor-4-dependent pattern in mice. Hepatology, 60(3):990-1002.
[21]CederbaumAI, 2012. Alcohol metabolism. Clin Liver Dis, 16(4):667-685.
[22]ChangL, XuDW, ZhuJJ, et al., 2020. Herbal therapy for the treatment of acetaminophen-associated liver injury: recent advances and future perspectives. Front Pharmacol, 11:313.
[23]ChangWJ, SongLJ, ChangXJ, et al., 2017. Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration. Lab Invest, 97(3):318-328.
[24]ChiewAL, GluudC, BrokJ, et al., 2018. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev, 2(2):Cd003328.
[25]ChiuH, GardnerCR, DambachDM, et al., 2003. Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense. Am J Physiol Gastrointest Liver Physiol, 285(5):G959-G966.
[26]ChowdhuryA, NabilaJ, Adelusi TemitopeI, et al., 2020. Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity. Pharmacol Res, 161:105102.
[27]CorcoranGB, WongBK, 1986. Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice. J Pharmacol Exp Ther, 238(1):54-61.
[28]CoverC, MansouriA, KnightTR, et al., 2005. Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther, 315(2):879-887.
[29]CoverC, LiuJ, FarhoodA, et al., 2006. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol, 216(1):98-107.
[30]DahlinDC, MiwaGT, LuAY, et al., 1984. N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA, 81(5):1327-1331.
[31]DambachDM, WatsonLM, GrayKR, et al., 2002. Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology, 35(5):1093-1103.
[32]DingY, LiQ, XuY, et al., 2016. Attenuating oxidative stress by paeonol protected against acetaminophen-induced hepatotoxicity in mice. PLoS ONE, 11(5):e0154375.
[33]DonahowerB, McCulloughSS, KurtenR, et al., 2006. Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am J Physiol Gastrointest Liver Physiol, 291(1):G102-G109.
[34]DonahowerBC, McCulloughSS, HenningsL, et al., 2010. Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. J Pharmacol Exp Ther, 334(1):33-43.
[35]DownsI, AwTY, LiuJF, et al., 2012. Vα14iNKT cell deficiency prevents acetaminophen-induced acute liver failure by enhancing hepatic glutathione and altering APAP metabolism. Biochem Biophys Res Commun, 428(2):245-251.
[36]DuK, RamachandranA, JaeschkeH, 2016. Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol, 10:148-156.
[37]DuK, RamachandranA, McGillMR, et al., 2017a. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol, 108:339-350.
[38]DuK, FarhoodA, JaeschkeH, 2017b. Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Arch Toxicol, 91(2):761-773.
[39]EhlingJ, BartneckM, WeiX, et al., 2014. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut, 63(12):1960-1971.
[40]FanXM, JiangYM, WangY, et al., 2014. Wuzhi tablet (Schisandra sphenanthera extract) protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of NRF2-ARE and p53/p21 pathways. Drug Metab Dispos, 42(12):1982-1990.
[41]FanXY, WangLD, HuangJB, et al., 2018. Pterostilbene reduces acetaminophen-induced liver injury by activating the Nrf2 antioxidative defense system via the AMPK/AKT/GSK3β pathway. Cell Physiol Biochem, 49(5):1943-1958.
[42]FengDC, WangY, WangH, et al., 2014. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. J Immunol, 193(5):2512-2518.
[43]FisherJE, MckenzieTJ, LillegardJB, et al., 2013. Role of Kupffer cells and Toll-like receptor 4 in acetaminophen-induced acute liver failure. J Surg Res, 180(1):147-155.
[44]FuCL, LiuY, LengJ, et al., 2018. Platycodin D protects acetaminophen-induced hepatotoxicity by inhibiting hepatocyte MAPK pathway and apoptosis in C57BL/6J mice. Biomed Pharmacother, 107:867-877.
[45]GaoRY, WangM, LiuQH, et al., 2020. Hypoxia-inducible factor-2α reprograms liver macrophages to protect against acute liver injury through the production of interleukin-6. Hepatology, 71(6):2105-2117.
[46]GongSH, LanT, ZengLY, et al., 2018. Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. J Hepatol, 69(1):51-59.
[47]HodgmanMJ, GarrardAR, 2012. A review of acetaminophen poisoning. Crit Care Clin, 28(4):499-516.
[48]HoltMP, ChengLL, JuC, 2008. Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol, 84(6):1410-1421.
[49]HouHS, LiaoCL, SytwuHK, et al., 2012. Deficiency of interleukin-15 enhances susceptibility to acetaminophen-induced liver injury in mice. PLoS ONE, 7(9):e44880.
[50]HuB, CollettiLM, 2008. Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice. Am J Physiol Gastrointest Liver Physiol, 295(1):G45-G53.
[51]HuJT, RamsheshVK, McGillMR, et al., 2016a. Low dose acetaminophen induces reversible mitochondrial dysfunction associated with transient c-Jun N-terminal kinase activation in mouse liver. Toxicol Sci, 150(1):204-215.
[52]HuJT, KholmukhamedovA, LindseyCC, et al., 2016b. Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury: protection by starch-desferal and minocycline. Free Radic Biol Med, 97:418-426.
[53]HuoY, YinS, YanM, et al., 2017. Protective role of p53 in acetaminophen hepatotoxicity. Free Radic Biol Med, 106:111-117.
[54]IgusaY, YamashinaS, IzumiK, et al., 2012. Loss of autophagy promotes murine acetaminophen hepatotoxicity. J Gastroenterol, 47(4):433-443.
[55]ImaedaAB, WatanabeA, SohailMA, et al., 2009. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest, 119(2):305-314.
[56]IshidaY, KondoT, OhshimaT, et al., 2002. A pivotal involvement of IFN-γ in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J, 16(10):1227-1236.
[57]IshidaY, KondoT, TsuneyamaK, et al., 2004. The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice. J Leukoc Biol, 75(1):59-67.
[58]JaeschkeH, LiuJ, 2007. Neutrophil depletion protects against murine acetaminophen hepatotoxicity: another perspective. Hepatology, 45(6):1588-1589.
[59]JaeschkeH, RamachandranA, 2020. Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. Food Chem Toxicol, 138:111240.
[60]JaeschkeH, McGillMR, RamachandranA, 2012. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev, 44(1):88-106.
[61]JaeschkeH, XieYC, McGillMR, 2014. Acetaminophen-induced liver injury: from animal models to humans. J Clin Transl Hepatol, 2(3):153-161.
[62]JaeschkeH, AkakpoJY, UmbaughDS, et al., 2020. Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure. Toxicol Sci, 174(2):159-167.
[63]JamesLP, LampsLW, McCulloughS, et al., 2003. Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse. Biochem Biophys Res Commun, 309(4):857-863.
[64]JamesLP, KurtenRC, LampsLW, et al., 2005. Tumour necrosis factor receptor 1 and hepatocyte regeneration in acetaminophen toxicity: a kinetic study of proliferating cell nuclear antigen and cytokine expression. Basic Clin Pharmacol Toxicol, 97(1):8-14.
[65]JollowDJ, MitchellJR, PotterWZ, et al., 1973. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther, 187(1):195-202.
[66]KangKY, ShinJK, LeeSM, 2019. Pterostilbene protects against acetaminophen-induced liver injury by restoring impaired autophagic flux. Food Chem Toxicol, 123:536-545.
[67]KarchJ, MolkentinJD, 2014. Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci USA, 111(29):10396-10397.
[68]KleinschmidtD, GiannouAD, McGeeHM, et al., 2017. A protective function of IL-22BP in ischemia reperfusion and acetaminophen-induced liver injury. J Immunol, 199(12):4078-4090.
[69]KonoH, ChenCJ, OntiverosF, et al., 2010. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest, 120(6):1939-1949.
[70]KrenkelO, MossanenJC, TackeF, 2014. Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg Nutr, 3(6):331-343.
[71]KruiswijkF, LabuschagneCF, VousdenKH, 2015. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol, 16(7):393-405.
[72]KubesP, MehalWZ, 2012. Sterile inflammation in the liver. Gastroenterology, 143(5):1158-1172.
[73]LawsonJA, FarhoodA, HopperRD, et al., 2000. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci, 54(2):509-516.
[74]LeeHC, LiaoCC, DayYJ, et al., 2018. IL-17 deficiency attenuates acetaminophen-induced hepatotoxicity in mice. Toxicol Lett, 292:20-30.
[75]LeeHC, YuHP, LiaoCC, et al., 2019. Escin protects against acetaminophen-induced liver injury in mice via attenuating inflammatory response and inhibiting ERK signaling pathway. Am J Transl Res, 11(8):5170-5182.
[76]LeeKK, ImaizumiN, ChamberlandSR, et al., 2015. Targeting mitochondria with methylene blue protects mice against acetaminophen-induced liver injury. Hepatology, 61(1):326-336.
[77]LemastersJJ, 1998. The mitochondrial permeability transition: from biochemical curiosity to pathophysiological mechanism. Gastroenterology, 115(3):783-786.
[78]LiaoCC, DayYJ, LeeHC, et al., 2017. ERK signaling pathway plays a key role in baicalin protection against acetaminophen-induced liver injury. Am J Chin Med, 45(1):105-121.
[79]LiuFC, YuHP, ChouAH, et al., 2020. Corilagin reduces acetaminophen-induced hepatotoxicity through MAPK and NF-κB signaling pathway in a mouse model. Am J Transl Res, 12(9):5597-5607.
[80]LiuZX, GovindarajanS, KaplowitzN, 2004. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology, 127(6):1760-1774.
[81]LuSC, 1999. Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J, 13(10):1169-1183.
[82]MarquesPE, AmaralSS, PiresDA, et al., 2012. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology, 56(5):1971-1982.
[83]Martin-MurphyBV, KominskyDJ, OrlickyDJ, et al., 2013. Increased susceptibility of natural killer T-cell-deficient mice to acetaminophen-induced liver injury. Hepatology, 57(4):1575-1584.
[84]MichaelSL, PumfordNR, MayeuxPR, et al., 1999. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology, 30(1):186-195.
[85]MichalopoulosGK, 2007. Liver regeneration. J Cell Physiol, 213(2):286-300.
[86]MoRD, LaiRT, LuJ, et al., 2018. Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury. Theranostics, 8(15):4170-4180.
[87]MolesA, TorresS, BauliesA, et al., 2018. Mitochondrial-lysosomal axis in acetaminophen hepatotoxicity. Front Pharmacol, 9:453.
[88]MooreJK, CraigDG, PrydeEA, et al., 2013. Persistently elevated troponin I in paracetamol hepatotoxicity: association with liver injury, organ failure, and outcome. Clin Toxicol, 51(7):532-539.
[89]MooreMN, 2008. Autophagy as a second level protective process in conferring resistance to environmentally-induced oxidative stress. Autophagy, 4(2):254-256.
[90]NiHM, BockusA, BoggessN, et al., 2012. Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology, 55(1):222-232.
[91]PatelSJ, LutherJ, BohrS, et al., 2016. A novel resolvin-based strategy for limiting acetaminophen hepatotoxicity. Clin Transl Gastroenterol, 7(3):e153.
[92]RamachandranA, JaeschkeH, 2019. Acetaminophen hepatotoxicity. Semin Liver Dis, 39(2):221-234.
[93]RamachandranA, LebofskyM, BainesCP, et al., 2011. Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury. Free Radic Res, 45(2):156-164.
[94]RasamisonR, BessonH, BerleurMP, et al., 2020. Analysis of fomepizole safety based on a 16-year post-marketing experience in france. Clin Toxicol, 58(7):742-747.
[95]ReubenA, TillmanH, FontanaRJ, et al., 2016. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med, 164(11):724-732.
[96]RezendeTP, doA. Corrêa JO, Aarestrup BJV, et al., 2014. Protective effects of Baccharis dracunculifolia leaves extract against carbon tetrachloride- and acetaminophen-induced hepatotoxicity in experimental animals. Molecules, 19(7):9257-9272.
[97]RyanPM, BourdiM, KorrapatiMC, et al., 2012. Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice. Chem Res Toxicol, 25(1):83-93.
[98]Saeedi SaraviSS, HasanvandA, ShahkaramiK, et al., 2016. The protective potential of metformin against acetaminophen-induced hepatotoxicity in BALB/C mice. Pharm Biol, 54(12):2830-2837.
[99]SaitoC, ZwingmannC, JaeschkeH, 2010. Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology, 51(1):246-254.
[100]ScheiermannP, BachmannM, GorenI, et al., 2013. Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury. Am J Pathol, 182(4):1107-1113.
[101]SchmidtLE, DalhoffK, PoulsenHE, 2002. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology, 35(4):876-882.
[102]SchneiderKM, ElfersC, GhallabA, et al., 2021. Intestinal dysbiosis amplifies acetaminophen-induced acute liver injury. Cell Mol Gastroenterol Hepatol, 11(4):909-933.
[103]SekiE, SchnablB, 2012. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol, 590(3):447-458.
[104]SharmaM, GadangV, JaeschkeA, 2012. Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity. Mol Pharmacol, 82(5):1001-1007.
[105]ShiXX, BaiHY, ZhaoM, et al., 2018. Treatment of acetaminophen-induced liver injury with exogenous mitochondria in mice. Transl Res, 196:31-41.
[106]ShinoharaM, YbanezMD, WinS, et al., 2010. Silencing glycogen synthase kinase-3β inhibits acetaminophen hepatotoxicity and attenuates JNK activation and loss of glutamate cysteine ligase and myeloid cell leukemia sequence 1. J Biol Chem, 285(11):8244-8255.
[107]SimpsonKJ, LukacsNW, McGregorAH, et al., 2000. Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis. J Pathol, 190(4):489-494.
[108]SmilksteinMJ, KnappGL, KuligKW, et al., 1988. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med, 319(24):1557-1562.
[109]SoedaJ, MouralidaraneA, RayS, et al., 2014. The beta-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice. Hepatology, 60(3):1023-1034.
[110]SunY, LiTY, SongL, et al., 2018. Liver-specific deficiency of unc-51 like kinase 1 and 2 protects mice from acetaminophen-induced liver injury. Hepatology, 67(6):2397-2413.
[111]TienYH, ChenBH, Wang HsuGS, et al., 2014. Hepatoprotective and anti-oxidant activities of Glossogyne tenuifolia against acetaminophen-induced hepatotoxicity in mice. Am J Chin Med, 42(6):1385-1398.
[112]TirmensteinMA, NelsonSD, 1989. Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3'-hydroxyacetanilide, in mouse liver. J Biol Chem, 264(17):9814-9819.
[113]TorresS, BauliesA, Insausti-UrkiaN, et al., 2019. Endoplasmic reticulum stress-induced upregulation of STARD1 promotes acetaminophen-induced acute liver failure. Gastroenterology, 157(2):552-568.
[114]TrnkaJ, BlaikieFH, SmithRAJ, et al., 2008. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic Biol Med, 44(7):1406-1419.
[115]UziD, BardaL, ScaiewiczV, et al., 2013. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol, 59(3):495-503.
[116]WalkerV, MillsGA, AndersonME, et al., 2017. The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis? Xenobiotica, 47(2):164-175.
[117]WangXF, SunR, WeiHM, et al., 2013. High-mobility group box 1 (HMGB1)-Toll-like receptor (TLR)4-interleukin (IL)-23-IL-17A axis in drug-induced damage-associated lethal hepatitis: interaction of γδ T cells with macrophages. Hepatology, 57(1):373-384.
[118]WangYQ, WeiJG, TuMJ, et al., 2018. Fucoidan alleviates acetaminophen-induced hepatotoxicity via oxidative stress inhibition and Nrf2 translocation. Int J Mol Sci, 19(12):4050.
[119]WaringWS, StephenAF, MalkowskaAM, et al., 2008. Acute ethanol coingestion confers a lower risk of hepatotoxicity after deliberate acetaminophen overdose. Acad Emerg Med, 15(1):54-58.
[120]WilliamsCD, BajtML, FarhoodA, et al., 2010. Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice. Liver Int, 30(9):1280-1292.
[121]WilliamsCD, BajtML, SharpeMR, et al., 2014. Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans. Toxicol Appl Pharmacol, 275(2):122-133.
[122]WinS, ThanTA, MinRWM, et al., 2016. c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src. Hepatology, 63(6):1987-2003.
[123]WinS, MinRWM, ChenCQ, et al., 2019. Expression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injury. J Clin Invest, 129(12):5278-5293.
[124]WoolbrightBL, JaeschkeH, 2018. Mechanisms of inflammatory liver injury and drug-induced hepatotoxicity. Curr Pharmacol Rep, 4(5):346-357.
[125]WuKC, HoYL, KuoYH, et al., 2018. Hepatoprotective effect of Ugonin M, a Helminthostachys zeylanica constituent, on acetaminophen-induced acute liver injury in mice. Molecules, 23(10):2420.
[126]XieYC, McGillMR, CookSF, et al., 2015. Time course of acetaminophen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells. Xenobiotica, 45(10):921-929.
[127]XuJ, ZhangXM, MonestierM, et al., 2011. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol, 187(5):2626-2631.
[128]YanAW, FoutsDE, BrandlJ, et al., 2011. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology, 53(1):96-105.
[129]YanMZ, HuoYZ, YinST, et al., 2018. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol, 17:274-283.
[130]YangRK, MikiK, HeX, et al., 2009. Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity. Crit Care, 13(2):R55.
[131]YangRK, ZhangST, KajanderH, et al., 2011. Ringer’s lactate improves liver recovery in a murine model of acetaminophen toxicity. BMC Gastroenterol, 11:125.
[132]YangRK, ZhangST, CotoiaA, et al., 2012. High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity. BMC Gastroenterol, 12:45.
[133]YangWT, TaoYD, WuY, et al., 2019. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair. Nat Commun, 10:1076.
[134]YeeSB, BourdiM, MassonMJ, et al., 2007. Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol, 20(5):734-744.
[135]YoshimotoS, LooTM, AtarashiK, et al., 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature, 499(7456):97-101.
[136]ZhangC, FengJ, DuJ, et al., 2018. Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell Mol Immunol, 15(11):973-982.
[137]ZhangJY, ZhangSM, BiJB, et al., 2017. Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice. Int Immunopharmacol, 45:26-33.
[138]ZigmondE, Samia-GrinbergS, Pasmanik-ChorM, et al., 2014. Infiltrating monocyte-derived macrophages and resident Kupffer cells display different ontogeny and functions in acute liver injury. J Immunol, 193(1):344-353.
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