758
Views
17
CrossRef citations to date
0
Altmetric
Review

Biomarkers of drug-induced liver injury: a mechanistic perspective through acetaminophen hepatotoxicity

& ORCID Icon
Pages 363-375 | Received 07 Sep 2020, Accepted 25 Nov 2020, Published online: 09 Dec 2020

References

  • Andrade RJ, Chalasani N, Bjornsson ES, et al. Drug-induced liver injury. Nat Rev Dis Primers. 2019;5(1):58.
  • Andrade RJ, Aithal GP, Björnsson ES, European Association for the Study of the Liver. Electronic address eee, clinical practice guideline panel c, panel m, representative EGB. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol. 2019;70(6):1222–1261.
  • Reuben A, Koch DG, Lee WM, Acute Liver Failure Study G. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065–2076.
  • Wei G, Bergquist A, Broome U, et al. Acute liver failure in Sweden: etiology and outcome. J Intern Med. 2007;262(3):393–401.
  • Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019;394(10201):869–881.
  • Stevens JL, Baker TK. The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov Today. 2009;14(3–4):162–167.
  • McGill MR, Jaeschke H. Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation. Expert Rev Mol Diagn. 2018;18(9):797–807.
  • Starkey Lewis PJ, Dear J, Platt V, et al. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology. 2011;54(5): 1767–1776.
  • Ward J, Kanchagar C, Veksler-Lublinsky I, et al. Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci U S A. 2014;111(33):12169–12174
  • Dear JW, Clarke JI, Francis B, et al. Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies. Lancet Gastroenterol Hepatol. 2018;3(2):104–113.
  • Umbaugh DS, Jaeschke H. Extracellular Vesicles: Roles and applications in drug-induced liver injury. Adv Clin Chem. in press;102:2021.
  • Bala S, Petrasek J, Mundkur S, et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology. 2012;56(5): 1946–1957.
  • Koberle V, Pleli T, Schmithals C, et al. Differential stability of cell-free circulating microRNAs: implications for their utilization as biomarkers. PLoS One. 2013;8(9):e75184.
  • Reuben A, Tillman H, Fontana RJ, et al. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med. 2016;164(11):724–732.
  • Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364–1372.
  • McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30(9):2174–2187.
  • Leung L, Kalgutkar AS, Obach RS. Metabolic activation in drug-induced liver injury. Drug Metab Rev. 2012;44(1):18–33.
  • Ramachandran A, Jaeschke H. Acetaminophen hepatotoxicity: a mitochondrial perspective. Adv Pharmacol. 2019;85:195–219.
  • Saito C, Lemasters JJ, Jaeschke H. c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 2010;246(1–2):8–17.
  • Hanawa N, Shinohara M, Saberi B, et al. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem. 2008;283(20):13565–13577.
  • Jaeschke H, Ramachandran A, Chao X, et al. Emerging and established modes of cell death during acetaminophen-induced liver injury. Arch Toxicol. 2019;93(12):3491–3502.
  • Ramachandran A, Visschers RGJ, Duan L, et al. Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives. J Clin Trans Res. 2018;4(1):75–100.
  • Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58(1):388–396.
  • Monshi MM, Faulkner L, Gibson A, et al. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology. 2013;57(2):727–739.
  • Grove JI, Aithal GP. Human leukocyte antigen genetic risk factors of drug-induced liver toxicology. Expert Opin Drug Metab Toxicol. 2015;11(3):395–409.
  • Uetrecht JP. New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system. Chem Res Toxicol. 1999;12(5):387–395.
  • Pohl LR. Drug-induced allergic hepatitis. Semin Liver Dis. 1990;10(4):305–315.
  • Park BK, Laverty H, Srivastava A, et al. Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity. Chem Biol Interact. 2011;192(1–2):30–36.
  • Mosedale M, Watkins PB. Drug-induced liver injury: advances in mechanistic understanding that will inform risk management. Clin Pharmacol Ther. 2017;101(4):469–480.
  • Castillo M, Lam YW, Dooley MA, et al. Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly. Clin Pharmacol Ther. 1995;57(6):636–644.
  • Heard KJ, Green JL, James LP, et al. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose. BMC Gastroenterol. 2011;11(1):20.
  • Heard K, Anderson VE, Lavonas EJ, et al. Serum paracetamol-protein adducts in ambulatory subjects: relationship to recent reported paracetamol use. Biomarkers. 2018;23(3):288–292.
  • Maria VA, Victorino RM. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut. 1997;41(4):534–540.
  • Ogese MO, Watkinson J, Lister A, et al. Development of an improved T-cell assay to assess the intrinsic immunogenicity of haptenic compounds. Toxicol Sci. 2020;175(2):266–278.
  • Uetrecht J, Kaplowitz N. Inhibition of immune tolerance unmasks drug-induced allergic hepatitis. Hepatology. 2015;62(2):346–348.
  • Mak A, Uetrecht J. Immune mechanisms of idiosyncratic drug-induced liver injury. J Clin Trans Res. 2017;3(1):145–156.
  • Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs–II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46(11):1331–1336.
  • Danan G, Benichou C. Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–1330.
  • Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2015;17(1):1.
  • Teschke R, Schulze J, Schwarzenboeck A, et al. Herbal hepatotoxicity: suspected cases assessed for alternative causes. Eur J Gastroenterol Hepatol. 2013;25(9):1093–1098.
  • Teschke R, Frenzel C, Wolff A, et al. Drug induced liver injury: accuracy of diagnosis in published reports. Ann Hepatol. 2014;13(2):248–255.
  • Teschke R, Danan G. Drug induced liver injury with analysis of alternative causes as confounding variables. Br J Clin Pharmacol. 2018;84(7):1467–1477.
  • Hayashi PH. Drug-induced liver injury network causality assessment: criteria and experience in the United States. Int J Mol Sci. 2016;17(2):201.
  • Danan G, Drug-Induced Liver TR. Injury: why is the roussel uclaf causality assessment method (RUCAM) still used 25 years after its launch? Drug Saf. 2018;41(8):735–743.
  • Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89(1):95–106.
  • Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148(7):1340–1352 e1347.
  • Kleiner DE, Chalasani NP, Lee WM, et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014;59(2):661–670.
  • Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–815.
  • Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871–876.
  • Pakravan N, Waring WS, Sharma S, et al. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol (Phila). 2008;46(8):697–702.
  • Antoine DJ, Dear JW, Lewis PS, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology. 2013;58(2):777–787.
  • Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20(10):1058–1063.
  • James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009;37(8):1779–1784.
  • Potter DW, Pumford NR, Hinson JA, et al. Epitope characterization of acetaminophen bound to protein and nonprotein sulfhydryl groups by an enzyme-linked immunosorbent assay. J Pharmacol Exp Ther. 1989;248(1):182–189.
  • Davern TJ 2nd, James LP, Hinson JA, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006;130(3):687–694.
  • Pumford NR, Roberts DW, Benson RW, et al. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen protein adducts in subcellular liver fractions following a hepatotoxic dose of acetaminophen. Biochem Pharmacol. 1990;40(3):573–579.
  • Muldrew KL, James LP, Coop L, et al. Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos. 2002;30(4):446–451.
  • McGill MR, Lebofsky M, Norris HR, et al. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications. Toxicol Appl Pharmacol. 2013;269(3):240–249.
  • Ni HM, McGill MR, Chao X, et al. Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. J Hepatol. 2016;65(2):354–362.
  • Pumford NR, Hinson JA, Potter DW, et al. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen-treated mice. J Pharmacol Exp Ther. 1989;248(1):190–196.
  • James LP, Farrar HC, Sullivan JE, et al. Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. J Clin Pharmacol. 2001;41(8):846–851.
  • Curry SC, Padilla-Jones A, Ruha AM, et al. The relationship between circulating acetaminophen-protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity. J Med Toxicol. 2019;15(3):143–155.
  • Schiodt FV, Ott P, Christensen E, et al. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther. 2002;71(4):221–225.
  • Chiew AL, James LP, Isbister GK, et al. Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5). J Hepatol. 72(3): 450–462. 2020.
  • Roberts DW, Lee WM, Hinson JA, et al. An immunoassay to rapidly measure acetaminophen protein adducts accurately identifies patients with acute liver injury or failure. Clin Gastroenterol Hepatol. 2017;15(4):555–562 e553.
  • Jaeschke H, Duan L, Akakpo JY, et al. The role of apoptosis in acetaminophen hepatotoxicity. Food Chem Toxicol. 2018;118:709–718.
  • Bonaldi T, Talamo F, Scaffidi P, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. Embo J. 2003;22(20):5551–5560.
  • Antoine DJ, Jenkins RE, Dear JW, et al. RETRACTED: molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol. 2012;56(5):1070–1079.
  • Teschke R, Eickhoff A, Brown AC, et al. Diagnostic biomarkers in liver injury by drugs, herbs, and alcohol: tricky dilemma after EMA correctly and officially retracted letter of support. Int J Mol Sci. 2019;21(1):1.
  • FDA. US food & drug administration letter of support initiative; Available from: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM517355.pdf
  • Craig DG, Lee P, Pryde EA, et al. Circulating apoptotic and necrotic cell death markers in patients with acute liver injury. Liver Int. 2011;31(8):1127–1136.
  • Saha B, Tornai D, Kodys K, et al. Biomarkers of macrophage activation and immune danger signals predict clinical outcomes in alcoholic hepatitis. Hepatology. 2019;70(4):1134–1149.
  • Bechmann LP, Marquitan G, Jochum C, et al. Apoptosis versus necrosis rate as a predictor in acute liver failure following acetaminophen intoxication compared with acute-on-chronic liver failure. Liver Int. 2008;28(5):713–716.
  • Xie Y, McGill MR, Dorko K, et al. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol. 2014;279(3):266–274.
  • Church RJ, Kullak-Ublick GA, Aubrecht J, et al. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: an international collaborative effort. Hepatology. 69(2): 760–773. 2019.
  • Woolbright BL, Bridges BW, Dunn W, et al. Cell death and prognosis of mortality in alcoholic hepatitis patients using plasma keratin-18. Gene Expr. 2017;17(4):301–312.
  • Nelson RL, Povey MS, Hopkinson DA, et al. Electrophoresis of human l-glutamate dehydrogenase: tissue distribution and preliminary population survey. Biochem Genet. 1977;15(1–2):87–91.
  • Racine-Samson L, Scoazec JY, D’Errico A, et al. The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue. Hepatology. 1996;24(1):104–113.
  • McGill MR, Sharpe MR, Williams CD, et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574–1583.
  • McGill MR, Staggs VS, Sharpe MR, et al., Acute Liver Failure Study G. Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome. Hepatology. 2014;60(4):1336–1345.
  • Church RJ, Schomaker SJ, Eaddy JS, et al. Glutamate dehydrogenase as a biomarker for mitotoxicity; insights from furosemide hepatotoxicity in the mouse. PLoS One. 2020;15(10):e0240562.
  • Harrill AH, Roach J, Fier I, et al. The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin Pharmacol Ther. 2012;92(2):214–220.
  • Lim AK. Abnormal liver function tests associated with severe rhabdomyolysis. World J Gastroenterol. 2020;26(10):1020–1028.
  • McGill MR, Li F, Sharpe MR, et al. Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans. Arch Toxicol. 2014;88(2):391–401.
  • Giffen PS, Pick CR, Price MA, et al. Alpha-glutathione S-transferase in the assessment of hepatotoxicity–its diagnostic utility in comparison with other recognized markers in the Wistar Han rat. Toxicol Pathol. 2002;30(3):365–372.
  • Bailey WJ, Holder D, Patel H, et al. A performance evaluation of three drug-induced liver injury biomarkers in the rat: alpha-glutathione S-transferase, arginase 1, and 4-hydroxyphenyl-pyruvate dioxygenase. Toxicol Sci. 2012;130(2):229–244.
  • Preisich P, Pinter Z, Biro G. [The role of sorbitol dehydrogenase in the diagnosis of liver diseases]. Orv Hetil. 1963;104:1272–1278.
  • Metushi IG, Nakagawa T, Uetrecht J. Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats. Chem Res Toxicol. 2012;25(11):2567–2576.
  • Lucena MI, Andrade RJ, Martinez C, et al. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology. 2008;48(2):588–596.
  • Beckett GJ, Foster GR, Hussey AJ, et al. Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage. Clin Chem. 1989;35(11):2186–2189.
  • Bhushan B, Walesky C, Manley M, et al. Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model. Am J Pathol. 2014;184(11):3013–3025.
  • Bhushan B, Apte U. Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities. Am J Pathol. 2019;189(4):719–729.
  • Schiodt FV, Ostapowicz G, Murray N, et al. Alpha-fetoprotein and prognosis in acute liver failure. Liver Transpl. 2006;12(12):1776–1781.
  • Bird TG, Muller M, Boulter L, et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med. 2018;10(454):454.
  • Woolbright BL, Jaeschke H. Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol. 2017;66(4):836–848.
  • Jaeschke H, Ramachandran A. Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. Food Chem Toxicol. 2020;138:111240.
  • Chauhan A, Sheriff L, Hussain MT, et al. The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure. Nat Commun. 2020;11(1):1939.
  • Yang W, Tao Y, Wu Y, et al. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair. Nat Commun. 2019;10(1): 1076.
  • Williams CD, Bajt ML, Sharpe MR, et al. Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans. Toxicol Appl Pharmacol. 2014;275(2):122–133.
  • Starkey Lewis P, Campana L, Aleksieva N, et al. Alternatively activated macrophages promote resolution of necrosis following acute liver injury. J Hepatol. 2020;73(2):349–360.
  • Antoniades CG, Quaglia A, Taams LS, et al. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatology. 2012;56(2): 735–746.
  • Ni HM, Woolbright BL, Williams J, et al. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol. 2014;61(3):617–625.
  • Brenner C, Galluzzi L, Kepp O, et al. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59(3):583–594.
  • Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7(3):311–317.
  • Lu XJ, Chen J, Yu CH, et al. LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor. J Exp Med. 2013;210(1):5–13.
  • Ovejero C, Cavard C, Perianin A, et al. Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of beta-catenin in the liver. Hepatology. 2004;40(1):167–176.
  • Sato Y, Watanabe H, Kameyama H, et al. Changes in serum LECT 2 levels during the early period of liver regeneration after adult living related donor liver transplantation. Transplant Proc. 2004;36(8):2357–2358.
  • Sato Y, Watanabe H, Kameyama H, et al. Serum LECT2 level as a prognostic indicator in acute liver failure. Transplant Proc. 2004;36(8):2359–2361.
  • Slowik V, Borude P, Jaeschke H, et al. Leukocyte cell derived chemotaxin-2 (Lect2) as a predictor of survival in adult acute liver failure. Transl Gastroenterol Hepatol. 2019;4:17.
  • Wen Y, Feng D, Wu H, et al. Defective initiation of liver regeneration in osteopontin-deficient mice after partial hepatectomy due to insufficient activation of IL-6/stat3 pathway. Int J Biol Sci. 2015;11(10):1236–1247.
  • Wang G, Zhao C, Chen S, et al. A preliminary in vivo study of the effects of OPN on rat liver regeneration induced by partial hepatectomy. Mol Biol Rep. 2016;43(12):1371–1382.
  • Arai M, Yokosuka O, Fukai K, et al. Gene expression profiles in liver regeneration with oval cell induction. Biochem Biophys Res Commun. 2004;317(2):370–376.
  • Woolbright BL, McGill MR, Sharpe MR, et al. Inflammatory mediator formation in surviving versus non-surviving acetaminophen overdose patients. Toxicol Sci. 2016;150(Suppl.1):352.
  • Lutkewitte AJ, Schweitzer GG, Kennon-McGill S, et al. Lipin deactivation after acetaminophen overdose causes phosphatidic acid accumulation in liver and plasma in mice and humans and enhances liver regeneration. Food Chem Toxicol. 2018;115:273–283.
  • Mohr AM, Mott JL. Overview of microRNA biology. Semin Liver Dis. 2015;35(1):3–11.
  • Wang K, Zhang S, Marzolf B, et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A. 2009;106(11):4402–4407.
  • Song L, Zhang Z, Zhang J, et al. Ratio of microRNA-122/155 in isoniazid-induced acute liver injury in mice. Exp Ther Med. 2016;12(2):889–894.
  • Russo MW, Steuerwald N, Norton HJ, et al. Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance. Liver Int. 2017;37(5):757–764.
  • Mitsugi R, Itoh T, Fujiwara R. MicroRNA-877-5p is involved in the trovafloxacin-induced liver injury. Toxicol Lett. 2016;263:34–43.
  • Kagawa T, Shirai Y, Oda S, et al. Identification of specific MicroRNA biomarkers in early stages of hepatocellular injury, cholestasis, and steatosis in rats. Toxicol Sci. 2018;166(1):228–239.
  • Yanez-Mo M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4(1):27066.
  • Stoorvogel W, Kleijmeer MJ, Geuze HJ, et al. The biogenesis and functions of exosomes. Traffic. 2002;3(5):321–330.
  • Cho YE, Kim SH, Lee BH, et al. Circulating plasma and exosomal microRNAs as indicators of drug-induced organ injury in rodent models. Biomol Ther (Seoul). 2017;25(4):367–373.
  • Thulin P, Hornby RJ, Auli M, et al. A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat. Biomarkers. 2017;22(5):461–469.
  • Duan L, Ramachandran A, Akakpo JY, et al. Role of extracellular vesicles in release of protein adducts after acetaminophen-induced liver injury in mice and humans. Toxicol Lett. 2019;301:125–132.
  • Hayakawa K, Esposito E, Wang X, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535(7613):551–555.
  • Dragoi D, Benesic A, Pichler G, et al. Proteomics analysis of monocyte-derived hepatocyte-like cells identifies integrin beta 3 as a specific biomarker for drug-induced liver injury by diclofenac. Front Pharmacol. 2018;9:699.
  • Winnike JH, Li Z, Wright FA, et al. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther. 2010;88(1):45–51.
  • Fannin RD, Russo M, O’Connell TM, et al. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology. 2010;51(1):227–236.
  • Badillo S, Banfai B, Birzele F, et al. An introduction to machine learning. Clin Pharmacol Ther. 2020;107(4): 871–885.
  • Wang R, Shao X, Zheng J, et al. A machine-learning approach to identify a prognostic cytokine signature that is associated with nivolumab clearance in patients with advanced melanoma. Clin Pharmacol Ther. 2020;107(4):978–987.
  • Wang X, Feng Y, Bajaj G, et al. Quantitative characterization of the exposure-response relationship for cancer immunotherapy: a case study of nivolumab in patients with advanced melanoma. CPT Pharmacometrics Syst Pharmacol. 2017;6(1):40–48.
  • O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439–445.
  • Albrecht W, Kappenberg F, Brecklinghaus T, et al. Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations. Arch Toxicol. 2019;93(6):1609–1637.
  • Lee WM. Acetaminophen and the U.S. acute liver failure study group: lowering the risks of hepatic failure. Hepatology. 2004;40(1):6–9.
  • Srungaram P, Rule JA, Yuan HJ, et al. Plasma osteopontin in acute liver failure. Cytokine. 2015;73(2):270–276.
  • Hoshino A, Kim HS, Bojmar L, et al. Extracellular vesicle and particle biomarkers define multiple human cancers. Cell. 2020;182(4):1044–1061.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.