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Review

Recent advances in biomarkers and therapeutic interventions for hepatic drug safety – false dawn or new horizon?

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Pages 625-634 | Received 05 Jan 2016, Accepted 23 Feb 2016, Published online: 17 Mar 2016

References

  • Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474–85.
  • Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002 Aug;36(2):451–455.
  • Meier Y, Cavallaro M, Roos M, et al. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol. 2005 Apr;61(2):135–143.
  • Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol. 2007 Mar;102(3):558–562. quiz 693.
  • Corsini A, Ganey P, Ju C, et al. Current challenges and controversies in drug-induced liver injury. Drug Saf. 2012 Dec 1;35(12):1099–1117.
  • Chen M, Suzuki A, Borlak J, et al. Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol. 2015 Aug;63(2):503–14.
  • Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method. Hepatology. 2010 Jun;51(6):2117–2126.
  • Moggs J, Moulin P, Pognan F, et al. Investigative safety science as a competitive advantage for Pharma. Expert Opin Drug Metab Toxicol. 2012 Sep;8(9):1071–1082.
  • Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968;12(1):135–161. Autumn
  • Watkins PB. Drug safety sciences and the bottleneck in drug development. Clin Pharmacol Ther. 2011 Jun;89(6):788–790.
  • Senior JR. Alanine aminotransferase: a clinical and regulatory tool for detecting liver injury-past, present, and future. Clin Pharmacol Ther. 2012 Sep;92(3):332–9.
  • Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf. 2011 Mar 1;34(3):243–252.
  • Merz M, Lee KR, Kullak-Ublick GA, et al. Methodology to assess clinical liver safety data. Drug Saf. 2014 Nov;37(Suppl 1):S33–45.
  • Avigan MI, Bjornsson ES, Pasanen M, et al. Liver safety assessment: required data elements and best practices for data collection and standardization in clinical trials. Drug Saf. 2014 Nov;37(Suppl 1):S19–31.
  • Watkins PB, Merz M, Avigan MI, et al. The clinical liver safety assessment best practices workshop: rationale, goals, accomplishments and the future. Drug Saf. 2014 Nov;37(Suppl 1):S1–7.
  • Ozer J, Ratner M, Shaw M, et al. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008;245(3):194–205.
  • Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994 Apr 6;271(13):992–998.
  • 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 Aug;92(2):214–220.
  • Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001 Mar;69(3):89–95.
  • Ratner M. FDA pharmacogenomics guidance sends clear message to industry. Nat Rev Drug Discov. 2005 May;4(5):359.
  • Matheis K, Laurie D, Andriamandroso C, et al. A generic operational strategy to qualify translational safety biomarkers. Drug Discov Today. 2011 Jul;16(13–14):600–608.
  • Antoine DJ, Mercer AE, Williams DP, et al. Mechanism-based bioanalysis and biomarkers for hepatic chemical stress. Xenobiotica. 2009 Aug;39(8):565–577.
  • Bonventre JV, Vaidya VS, Schmouder R, et al. Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010 May;28(5):436–440.
  • Vaidya VS, Ozer JS, Dieterle F, et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol. 2010 May;28(5):478–485.
  • Urban TJ, Shen Y, Stolz A, et al. Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet Genomics. 2012 Nov;22(11):784–795.
  • Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568–579.
  • Alfirevic A, Park BK, Pirmohamed M, et al. Explanation for HLA-B*57:01-linked immune-mediated abacavir-induced hypersensitivity. Pharmacogenomics. 2012 Nov;13(14):1567–1569.
  • Harrill AH, Watkins PB, Su S, et al. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. 2009 Sep;19(9):1507–1515.
  • Harrill AH, Desmet KD, Wolf KK, et al. A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models. Toxicol Sci. 2012 Dec;130(2):416–426.
  • Starkey Lewis PJ, Merz M, Couttet P, et al. Serum microRNA biomarkers for drug-induced liver injury. Clin Pharmacol Ther. 2012 Sep;92(3):291–293.
  • Zen K, Zhang CY. Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers. Med Res Rev. 2012 Mar;32(2):326–348.
  • 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 Mar 17;106(11):4402–7.
  • Zhang Y, Jia Y, Zheng R, et al. Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem. 2010 Dec;56(12):1830–1838.
  • Antoine DJ, Dear JW, Starkey LP, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology. 2013;58:777–787 (PMCID: PMC3842113).
  • Dear JW, Antoine DJ, Starkey-Lewis P, et al. Letter to the Editor: Early detection of paracetamol toxicity using circulating liver microRNA and markers of cell necrosis. Br J Clin Pharmacol. 2013 Jul 23. doi:10.1111/bcp.12214.
  • Thulin P, Nordahl G, Gry M, et al. Keratin-18 and microRNA-122 complement alanine aminotransferase (ALT) as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int. 2014;34:367–378 (PMID: 24118944).
  • Arrese M, Eguchi A, Feldstein AE. Circulating microRNAs: emerging biomarkers of liver disease. Semin Liver Dis. 2015 Feb;35(1):43–54.
  • Vliegenthart ADB, Starkey LP, Tucker CS, et al. Retro-orbital blood acquisition facilitates circulating microRNA measurement in zebrafish with paracetamol hepatotoxicity. Zebrafish. 2014;11:219–226 (PMCID: PMC4119933).
  • Sharkey JW, Antoine DJ, Park BK. Validation of the isolation and quantification of kidney enriched miRNAs for use as biomarkers. Biomarkers. 2012 May;17(3):231–239.
  • Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191–195.
  • Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–251.
  • Yang H, Antoine DJ, Andersson U, et al. The many faces of HMGB1: molecular structure-function activity in inflammation, apoptosis and chemotaxis. J Leukoc Biol. 2013;93:865–873 (PMCID: PMC4051189).
  • Nyström S, Antoine DJ, Lundbäck P, et al. TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis. EMBO J. 2013 Jan 9;32(1):86–99.
  • Lu B, Nakamura T, Inouye K, et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012 Aug 30;488(7413):670–674.
  • Yang H, Lundbäck P, Ottosson L, et al. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med. 2012;18(1):250–259.
  • Venereau E, Casalgrandi M, Schiraldi M, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med. 2012 Aug 27;209(9):1519–1528.
  • Antoine DJ, Harris HE, Andersson U, et al. A systematic nomenclature for the redox states of High Mobility Group Box (HMGB) proteins. Mol Med. 2014;20(1):135–137.
  • Bonaldi T, Talamo F, Scaffidi P, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO Journal. 2003;22(20):5551–5560.
  • Lu B, Antoine DJ, Kwan K, et al. JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3068–3073.
  • Antoine DJ, Williams DP, Kipar A, et al. High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci. 2009 Dec;112(2):521–531.
  • Antoine DJ, Williams DP, Kipar A, et al. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. Mol Med. 2010;16(11–12):479–490.
  • 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 Aug;58(2):777–87.
  • Antoine DJ, Jenkins RE, Dear JW, et al. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol. 2012 May;56(5):1070–9.
  • Huebener P, Pradere JP, Hernandez C, et al. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J Clin Invest. 2015 Feb;125(2):539–550.
  • Yang H, Wang H, Ju Z, et al. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. J Exp Med. 2015 Jan 12;212(1):5–14.
  • Ge X, Antoine DJ, Lu Y, et al. High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD). J Biol Chem. 2014 Aug 15;289(33):22672–22691.
  • Woolbright BL, Antoine DJ, Jenkins RE, et al. Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice. Toxicol Appl Pharmacol. 2013 Dec 15;273(3):524–531.
  • Stutchfield BM, Antoine DJ, Mackinnon AC, et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology. 2015 Dec;149(7):1896–909 e14.
  • Chalasani N, Kahi C, Francois F, et al. Model for end-stage liver disease (MELD) for predicting mortality in patients with acute variceal bleeding. Hepatology. 2002 May;35(5):1282–1284.
  • McWilliam SJ, Antoine DJ, Sabbisetti V, et al. Mechanism-based urinary biomarkers to identify the potential for aminoglycoside-induced nephrotoxicity in premature neonates: a proof-of-concept study. PLoS ONE. 2012;7(8):e43809.
  • Sabbisetti VS, Waikar SS, Antoine DJ, et al. Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol. 2014 Oct;25(10):2177–2186.
  • Antoine DJ, Sabbisetti VS, Francis B, et al. Circulating kidney injury molecule 1 predicts prognosis and poor outcome in patients with acetaminophen-induced liver injury. Hepatology. 2015 Aug;62(2):591–599.
  • Ku NO, Strnad P, Zhong BH, et al. Keratins let liver live: mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies. Hepatology. 2007;46(5):1639–1649.
  • Caulín C, Salvesen GS, Oshima RG. Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithelial cell apoptosis. J Cell Biol. 1997;138(6):1379–1394.
  • Schutte B, Henfling M, Kölgen W, et al. Keratin 8/18 breakdown and reorganization during apoptosis. Exp Cell Res. 2004;297(1):11–26.
  • Wieckowska A, Zein NN, Yerian LM, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006;44(1):27–33.
  • Cummings J, Hodgkinson C, Odedra R, et al. Preclinical evaluation of M30 and M65 ELISAs as biomarkers of drug induced tumor cell death and antitumor activity. Mol Cancer Ther. 2008;7(3):455–463.
  • Ku NO, Michie SA, Soetikno RM, et al. Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. J Clin Invest. 1996 Aug 15;98(4):1034–1046.
  • Strnad P, Zhou Q, Hanada S, et al. Keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations. Gastroenterology. 2010 Sep;139(3):828–35, 35 e1–3.
  • Bechmann LP, Jochum C, Kocabayoglu P, et al. Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol. 2010 Oct;53(4):639–647.
  • Feldman BF. Cerebrospinal fluid. In: Kaneko J, editor. Clinical biochemistry of domestic animals. San Diego: Academic Press; 1989. p. 835–865.
  • Stonard MD. Assessment of nephrotoxicity. In: Evans GO, editor. Animal clinical chemistry. London: Taylor & Francis; 1996. p. 87–89.
  • Schmidt ES, Schmidt FW. Glutamate dehydrogenase: biochemical and clinical aspects of an interesting enzyme. Clin Chim Acta. 1988 Mar 31;173(1):43–55.
  • Schomaker S, Warner R, Bock J, et al. Assessment of emerging biomarkers of liver injury in human subjects. Toxicol Sci. 2013 Apr;132(2):276–283.
  • O’Brien PJ, Slaughter MR, Polley SR, et al. Advantages of glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. Lab Anim. 2002 Jul;36(3):313–321.
  • 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 Apr 2;122(4):1574–1583.
  • Singhal R, Harrill AH, Menguy-Vacheron F, et al. Benign elevations in serum aminotransferases and biomarkers of hepatotoxicity in healthy volunteers treated with cholestyramine. BMC Pharmacol Toxicol. 2014;15:42. doi:10.1186/2050-6511-15-42.
  • Jaeschke H, McGill MR. Serum glutamate dehydrogenase–biomarker for liver cell death or mitochondrial dysfunction? Toxicol Sci. 2013 Jul;134(1):221–222.
  • Chen C, Krausz KW, Shah YM, et al. Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity. Chem Res Toxicol. 2009 Apr;22(4):699–707.
  • 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 Feb;88(2):391–401.
  • Dear JW, Antoine DJ. Stratification of paracetamol overdose patients using new toxicity biomarkers: current candidates and future challenges. Expert Rev Clin Pharmacol. 2014 Mar;7(2):181–189.
  • Thomas JA, Pope C, Wojtacha D, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology. 2011 Jun;53(6):2003–2015.
  • Aithal GP, Rawlins MD, Day CP. Accuracy of hepatic adverse drug reaction reporting in one English health region. BMJ. 1999 Dec 11;319(7224):1541.
  • Antoine DJ, Lewis PS, Goldring CE, et al. Are we closer to finding biomarkers for identifying acute drug-induced liver injury? Biomark Med. 2013 Jun;7(3):383–386.
  • Watkins PB, Seligman PJ, Pears JS, et al. Using controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology. 2008 Nov;48(5):1680–1689.
  • Mandrekar SJ, Dahlberg SE, Simon R. Improving clinical trial efficiency: thinking outside the box. Am Soc Clin Oncol Educ Book. 2015;35:e141–7.

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