title: Current concepts of mechanisms in drug-induced hepatotoxicity.
abstract: Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland. stefan.russmann@usz.ch
authors.forename: Stefan
authors.initials: S
authors.lastname: Russmann
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: Ignazio
authors.initials: I
authors.lastname: Grattagliano
mesh_terms: D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D009336:Necrosis; D012307:Risk Factors
references.citation: J Gastroenterol Hepatol. 2008 Mar;23(3):366-73
references.pmid: 18318821
references.citation: Science. 1996 Jul 5;273(5271):59-63
references.pmid: 8658196
references.citation: Dig Dis Sci. 2001 Dec;46(12):2758-61
references.pmid: 11768270
references.citation: J Hepatol. 2005 Aug;43(2):342-57
references.pmid: 15975683
references.citation: Mol Pharmacol. 2001 Mar;59(3):627-35
references.pmid: 11179459
references.citation: Semin Liver Dis. 2002;22(2):115-22
references.pmid: 12016543
references.citation: Semin Perinatol. 1999 Apr;23(2):100-12
references.pmid: 10331463
references.citation: Gut. 2009 Apr;58(4):537-44
references.pmid: 18987030
references.citation: Semin Liver Dis. 2003 Aug;23(3):217-26
references.pmid: 14523675
references.citation: Transplantation. 2001 Jun 27;71(12):1816-20
references.pmid: 11455263
references.citation: Semin Liver Dis. 1981 May;1(2):134-42
references.pmid: 7347017
references.citation: Eur J Clin Nutr. 2004 Feb;58(2):238-43
references.pmid: 14749742
references.citation: J Clin Invest. 1998 Jun 15;101(12):2790-9
references.pmid: 9637713
references.citation: Drug Metab Rev. 1992;24(1):5-47
references.pmid: 1555494
references.citation: J Cell Physiol. 2000 Jan;182(1):41-9
references.pmid: 10567915
references.citation: Hum Mol Genet. 2007 May 15;16(10):1188-200
references.pmid: 17409198
references.citation: Hepatology. 1995 May;21(5):1450-4
references.pmid: 7737652
references.citation: Gastroenterology. 2008 May;134(6):1641-54
references.pmid: 18471544
references.citation: Toxicol Appl Pharmacol. 2007 Apr 1;220(1):92-107
references.pmid: 17275868
references.citation: Chem Res Toxicol. 2001 Jun;14(6):694-701
references.pmid: 11409940
references.citation: Hepatology. 2004 May;39(5):1430-40
references.pmid: 15122773
references.citation: Toxicol Sci. 2002 Oct;69(2):448-59
references.pmid: 12377994
references.citation: Proteomics. 2008 Feb;8(3):555-68
references.pmid: 18232058
references.citation: Eur Rev Med Pharmacol Sci. 2008 Jul-Aug;12(4):245-9
references.pmid: 18727456
references.citation: FASEB J. 1995 Feb;9(2):246-52
references.pmid: 7781927
references.citation: Arch Biochem Biophys. 2005 Jan 15;433(2):397-412
references.pmid: 15581596
references.citation: J Hepatol. 2007 Jul;47(1):128-34
references.pmid: 17400324
references.citation: Clin Pharmacol Ther. 2006 Jun;79(6):521-8
references.pmid: 16765139
references.citation: Gut. 1988 Sep;29(9):1153-7
references.pmid: 3197987
references.citation: Anesth Analg. 1997 Jan;84(1):173-8
references.pmid: 8989020
references.citation: Crit Rev Toxicol. 2007 Jun;37(5):413-59
references.pmid: 17612954
references.citation: N Engl J Med. 2008 Feb 7;358(6):568-79
references.pmid: 18256392
references.citation: Pharmacoepidemiol Drug Saf. 2006 Apr;15(4):231-3
references.pmid: 16552791
references.citation: Semin Liver Dis. 2002;22(2):123-36
references.pmid: 12016544
references.citation: Hepatology. 2000 Mar;31(3):674-83
references.pmid: 10706558
references.citation: J Hepatol. 1997;26 Suppl 1:23-30
references.pmid: 9138125
references.citation: Hepatology. 2004 Oct;40(4):773
references.pmid: 15382161
references.citation: J Biol Chem. 2001 Mar 9;276(10):7320-6
references.pmid: 11058599
references.citation: J Hepatol. 2002 Dec;37(6):741-7
references.pmid: 12445413
references.citation: J Leukoc Biol. 2004 Jan;75(1):59-67
references.pmid: 14557383
references.citation: Toxicol Pathol. 2005;33(1):41-51
references.pmid: 15805055
references.citation: N Engl J Med. 2008 Aug 21;359(8):789-99
references.pmid: 18650507
references.citation: Semin Liver Dis. 2002 Feb;22(1):27-42
references.pmid: 11928077
references.citation: JAMA. 2002 May 1;287(17):2273-5
references.pmid: 11980528
references.citation: Toxicol Appl Pharmacol. 2008 Sep 15;231(3):336-43
references.pmid: 18572215
references.citation: Gastroenterol Clin Biol. 2000 Nov;24(11):1052-91
references.pmid: 11139675
references.citation: Drug Saf. 2001;24(7):483-90
references.pmid: 11444721
references.citation: Pharmacogenet Genomics. 2007 Jan;17(1):47-60
references.pmid: 17264802
references.citation: J Pharmacol Exp Ther. 2001 Aug;298(2):737-43
references.pmid: 11454938
references.citation: Hepatology. 2005 Apr;41(4):925-35
references.pmid: 15799034
references.citation: J Hepatol. 2003 Oct;39(4):571-9
references.pmid: 12971968
references.citation: Phytomedicine. 2008 Jan;15(1-2):120-31
references.pmid: 18055189
references.citation: Hepatology. 2000 Aug;32(2):303-11
references.pmid: 10915737
references.citation: J Bioenerg Biomembr. 1999 Aug;31(4):305-19
references.pmid: 10665521
references.citation: Hepatology. 2007 Feb;45(2):391-403
references.pmid: 17256749
references.citation: Food Chem Toxicol. 2003 Aug;41(8):1123-32
references.pmid: 12842180
references.citation: Semin Liver Dis. 2001;21(1):57-69
references.pmid: 11296697
references.citation: J Hepatol. 2003 May;38(5):694-5
references.pmid: 12713887
references.citation: J Hepatol. 2003 Jul;39(1):62-7
references.pmid: 12821045
references.citation: Science. 2002 Oct 11;298(5592):422-4
references.pmid: 12376703
references.citation: Nat Cell Biol. 2004 Feb;6(2):146-53
references.pmid: 14743220
references.citation: J Exp Med. 1997 Apr 21;185(8):1481-6
references.pmid: 9126928
references.citation: Hepatology. 2006 Dec;44(6):1581-8
references.pmid: 17133470
references.citation: J Hepatol. 1999 Oct;31(4):760-70
references.pmid: 10551404
references.citation: Ann Intern Med. 2001 Jul 3;135(1):68-9
references.pmid: 11434754
references.citation: FASEB J. 2002 Aug;16(10):1227-36
references.pmid: 12153990
references.citation: Hepatology. 2008 Oct;48(4):1292-301
references.pmid: 18785192
references.citation: Hepatology. 2001 Apr;33(4):808-15
references.pmid: 11283843
references.citation: Hepatology. 2002 Nov;36(5):1190-6
references.pmid: 12395329
references.citation: J Cell Physiol. 2007 Nov;213(2):286-300
references.pmid: 17559071
references.citation: Clin Pharmacol Ther. 1991 Jan;49(1):13-7
references.pmid: 1988235
references.citation: Biochem Pharmacol. 1996 Oct 25;52(8):1147-54
references.pmid: 8937421
references.citation: J Pharmacol Exp Ther. 1991 Nov;259(2):894-904
references.pmid: 1941634
references.citation: J Pharmacol Exp Ther. 2006 Dec;319(3):1191-9
references.pmid: 16990511
references.citation: Curr Opin Allergy Clin Immunol. 2003 Aug;3(4):235-42
references.pmid: 12865765
references.citation: Drug Saf. 2002;25(9):633-48
references.pmid: 12137558
references.citation: Hepatology. 2007 Feb;45(2):412-21
references.pmid: 17366662
references.citation: Lancet. 2002 Mar 2;359(9308):727-32
references.pmid: 11888582
references.citation: Clin Pharmacol Ther. 2000 Jun;67(6):591-9
references.pmid: 10872641
references.citation: Curr Drug Metab. 2005 Jun;6(3):161-225
references.pmid: 15975040
references.citation: Semin Liver Dis. 2003 May;23(2):183-94
references.pmid: 12800071
references.citation: Clin Pharmacol Ther. 2001 Apr;69(4):223-31
references.pmid: 11309550
references.citation: J Pharmacol Exp Ther. 2006 Dec;319(3):1413-23
references.pmid: 16971508
references.citation: Gastroenterology. 2006 Jul;131(1):165-78
references.pmid: 16831600
references.citation: J Pharmacol Exp Ther. 1995 Feb;272(2):930-8
references.pmid: 7853211
references.citation: Ann Intern Med. 2002 Dec 17;137(12):947-54
references.pmid: 12484709
references.citation: Hepatology. 2006 Mar;43(3):618-31
references.pmid: 16496329
references.citation: Hepatology. 2006 Aug;44(2):379-88
references.pmid: 16871587
references.citation: Hepatology. 1995 Apr;21(4):1045-50
references.pmid: 7705777
references.citation: Am J Clin Pathol. 2004 Feb;121(2):211-9
references.pmid: 14983934
references.citation: Cell Tissue Res. 2004 May;316(2):197-209
references.pmid: 15015077
references.citation: J Lab Clin Med. 1995 Mar;125(3):378-83
references.pmid: 7897304
references.citation: N Engl J Med. 1999 Jun 3;340(22):1723-31
references.pmid: 10352164
references.citation: Hepatology. 2006 Jun;43(6):1220-30
references.pmid: 16729305
references.citation: Hepatology. 2003 Jun;37(6):1425-34
references.pmid: 12774022
references.citation: Hepatology. 2002 Apr;35(4):883-9
references.pmid: 11915035
references.citation: Eur J Gastroenterol Hepatol. 2003 Sep;15(9):1033-6
references.pmid: 12923378
references.citation: Anesth Analg. 2002 Feb;94(2):243-9, table of contents
references.pmid: 11812677
references.citation: J Biol Chem. 1999 Aug 6;274(32):22532-8
references.pmid: 10428830
references.citation: Hepatology. 2002 Jul;36(1):55-64
references.pmid: 12085349
references.citation: Cell Biol Toxicol. 1999;15(6):367-73
references.pmid: 10811531
references.citation: Digestion. 2007;75(4):232-7
references.pmid: 18004067
references.citation: Clin Sci (Lond). 2008 Apr;114(7):457-66
references.pmid: 18302533
references.citation: Dig Liver Dis. 2006 Jun;38(6):363-73
references.pmid: 16631422
references.citation: J Hepatol. 2007 May;46(5):858-68
references.pmid: 17275124
references.citation: Clin Liver Dis. 2007 Aug;11(3):577-96, vii
references.pmid: 17723921
references.citation: Gastroenterology. 2000 Feb;118(2):422-30
references.pmid: 10648470
references.citation: Hepatology. 2004 May;39(5):1267-76
references.pmid: 15122755
references.citation: Hepatology. 2004 Jun;39(6):1603-12
references.pmid: 15185301
references.citation: Toxicol Sci. 2001 Jan;59(1):169-77
references.pmid: 11134556
references.citation: Pharmacogenomics. 2008 Mar;9(3):359-63
references.pmid: 18303971
references.citation: Biochem Biophys Res Commun. 1996 Sep 24;226(3):695-702
references.pmid: 8831677
references.citation: Drug Metab Dispos. 2007 Oct;35(10):1963-9
references.pmid: 17627974
references.citation: Hepatology. 2006 Jul;44(1):27-33
references.pmid: 16799979
references.citation: Toxicology. 2008 Apr 3;246(1):24-33
references.pmid: 18083283
references.citation: J Hepatol. 2007 Oct;47(4):521-6
references.pmid: 17692989
references.citation: Nat Rev Drug Discov. 2005 Jun;4(6):489-99
references.pmid: 15931258
references.citation: J Toxicol Clin Toxicol. 1996;34(3):301-5
references.pmid: 8667468
references.citation: Expert Opin Drug Metab Toxicol. 2006 Aug;2(4):493-503
references.pmid: 16859400
references.citation: World J Gastroenterol. 2008 Jan 7;14(1):38-45
references.pmid: 18176959
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4611-6
references.pmid: 11287661
references.citation: Hepatology. 1999 Feb;29(2):451-63
references.pmid: 9918922
references.citation: Hepatology. 2003 Apr;37(4):924-30
references.pmid: 12668988
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G583-9
references.pmid: 16537970
references.citation: Gut. 2007 Jul;56(7):982-90
references.pmid: 17185352
references.citation: Clin Pharmacol Ther. 2000 Apr;67(4):432-7
references.pmid: 10801254