Current concepts of mechanisms in drug-induced hepatotoxicity.
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.
Russmann
Stefan
S
Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland. stefan.russmann@usz.ch
Kullak-Ublick
Gerd A
GA
Grattagliano
Ignazio
I
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
J Gastroenterol Hepatol. 2008 Mar;23(3):366-73
18318821
Science. 1996 Jul 5;273(5271):59-63
8658196
Dig Dis Sci. 2001 Dec;46(12):2758-61
11768270
J Hepatol. 2005 Aug;43(2):342-57
15975683
Mol Pharmacol. 2001 Mar;59(3):627-35
11179459
Semin Liver Dis. 2002;22(2):115-22
12016543
Semin Perinatol. 1999 Apr;23(2):100-12
10331463
Gut. 2009 Apr;58(4):537-44
18987030
Semin Liver Dis. 2003 Aug;23(3):217-26
14523675
Transplantation. 2001 Jun 27;71(12):1816-20
11455263
Semin Liver Dis. 1981 May;1(2):134-42
7347017
Eur J Clin Nutr. 2004 Feb;58(2):238-43
14749742
J Clin Invest. 1998 Jun 15;101(12):2790-9
9637713
Drug Metab Rev. 1992;24(1):5-47
1555494
J Cell Physiol. 2000 Jan;182(1):41-9
10567915
Hum Mol Genet. 2007 May 15;16(10):1188-200
17409198
Hepatology. 1995 May;21(5):1450-4
7737652
Gastroenterology. 2008 May;134(6):1641-54
18471544
Toxicol Appl Pharmacol. 2007 Apr 1;220(1):92-107
17275868
Chem Res Toxicol. 2001 Jun;14(6):694-701
11409940
Hepatology. 2004 May;39(5):1430-40
15122773
Toxicol Sci. 2002 Oct;69(2):448-59
12377994
Proteomics. 2008 Feb;8(3):555-68
18232058
Eur Rev Med Pharmacol Sci. 2008 Jul-Aug;12(4):245-9
18727456
FASEB J. 1995 Feb;9(2):246-52
7781927
Arch Biochem Biophys. 2005 Jan 15;433(2):397-412
15581596
J Hepatol. 2007 Jul;47(1):128-34
17400324
Clin Pharmacol Ther. 2006 Jun;79(6):521-8
16765139
Gut. 1988 Sep;29(9):1153-7
3197987
Anesth Analg. 1997 Jan;84(1):173-8
8989020
Crit Rev Toxicol. 2007 Jun;37(5):413-59
17612954
N Engl J Med. 2008 Feb 7;358(6):568-79
18256392
Pharmacoepidemiol Drug Saf. 2006 Apr;15(4):231-3
16552791
Semin Liver Dis. 2002;22(2):123-36
12016544
Hepatology. 2000 Mar;31(3):674-83
10706558
J Hepatol. 1997;26 Suppl 1:23-30
9138125
Hepatology. 2004 Oct;40(4):773
15382161
J Biol Chem. 2001 Mar 9;276(10):7320-6
11058599
J Hepatol. 2002 Dec;37(6):741-7
12445413
J Leukoc Biol. 2004 Jan;75(1):59-67
14557383
Toxicol Pathol. 2005;33(1):41-51
15805055
N Engl J Med. 2008 Aug 21;359(8):789-99
18650507
Semin Liver Dis. 2002 Feb;22(1):27-42
11928077
JAMA. 2002 May 1;287(17):2273-5
11980528
Toxicol Appl Pharmacol. 2008 Sep 15;231(3):336-43
18572215
Gastroenterol Clin Biol. 2000 Nov;24(11):1052-91
11139675
Drug Saf. 2001;24(7):483-90
11444721
Pharmacogenet Genomics. 2007 Jan;17(1):47-60
17264802
J Pharmacol Exp Ther. 2001 Aug;298(2):737-43
11454938
Hepatology. 2005 Apr;41(4):925-35
15799034
J Hepatol. 2003 Oct;39(4):571-9
12971968
Phytomedicine. 2008 Jan;15(1-2):120-31
18055189
Hepatology. 2000 Aug;32(2):303-11
10915737
J Bioenerg Biomembr. 1999 Aug;31(4):305-19
10665521
Hepatology. 2007 Feb;45(2):391-403
17256749
Food Chem Toxicol. 2003 Aug;41(8):1123-32
12842180
Semin Liver Dis. 2001;21(1):57-69
11296697
J Hepatol. 2003 May;38(5):694-5
12713887
J Hepatol. 2003 Jul;39(1):62-7
12821045
Science. 2002 Oct 11;298(5592):422-4
12376703
Nat Cell Biol. 2004 Feb;6(2):146-53
14743220
J Exp Med. 1997 Apr 21;185(8):1481-6
9126928
Hepatology. 2006 Dec;44(6):1581-8
17133470
J Hepatol. 1999 Oct;31(4):760-70
10551404
Ann Intern Med. 2001 Jul 3;135(1):68-9
11434754
FASEB J. 2002 Aug;16(10):1227-36
12153990
Hepatology. 2008 Oct;48(4):1292-301
18785192
Hepatology. 2001 Apr;33(4):808-15
11283843
Hepatology. 2002 Nov;36(5):1190-6
12395329
J Cell Physiol. 2007 Nov;213(2):286-300
17559071
Clin Pharmacol Ther. 1991 Jan;49(1):13-7
1988235
Biochem Pharmacol. 1996 Oct 25;52(8):1147-54
8937421
J Pharmacol Exp Ther. 1991 Nov;259(2):894-904
1941634
J Pharmacol Exp Ther. 2006 Dec;319(3):1191-9
16990511
Curr Opin Allergy Clin Immunol. 2003 Aug;3(4):235-42
12865765
Drug Saf. 2002;25(9):633-48
12137558
Hepatology. 2007 Feb;45(2):412-21
17366662
Lancet. 2002 Mar 2;359(9308):727-32
11888582
Clin Pharmacol Ther. 2000 Jun;67(6):591-9
10872641
Curr Drug Metab. 2005 Jun;6(3):161-225
15975040
Semin Liver Dis. 2003 May;23(2):183-94
12800071
Clin Pharmacol Ther. 2001 Apr;69(4):223-31
11309550
J Pharmacol Exp Ther. 2006 Dec;319(3):1413-23
16971508
Gastroenterology. 2006 Jul;131(1):165-78
16831600
J Pharmacol Exp Ther. 1995 Feb;272(2):930-8
7853211
Ann Intern Med. 2002 Dec 17;137(12):947-54
12484709
Hepatology. 2006 Mar;43(3):618-31
16496329
Hepatology. 2006 Aug;44(2):379-88
16871587
Hepatology. 1995 Apr;21(4):1045-50
7705777
Am J Clin Pathol. 2004 Feb;121(2):211-9
14983934
Cell Tissue Res. 2004 May;316(2):197-209
15015077
J Lab Clin Med. 1995 Mar;125(3):378-83
7897304
N Engl J Med. 1999 Jun 3;340(22):1723-31
10352164
Hepatology. 2006 Jun;43(6):1220-30
16729305
Hepatology. 2003 Jun;37(6):1425-34
12774022
Hepatology. 2002 Apr;35(4):883-9
11915035
Eur J Gastroenterol Hepatol. 2003 Sep;15(9):1033-6
12923378
Anesth Analg. 2002 Feb;94(2):243-9, table of contents
11812677
J Biol Chem. 1999 Aug 6;274(32):22532-8
10428830
Hepatology. 2002 Jul;36(1):55-64
12085349
Cell Biol Toxicol. 1999;15(6):367-73
10811531
Digestion. 2007;75(4):232-7
18004067
Clin Sci (Lond). 2008 Apr;114(7):457-66
18302533
Dig Liver Dis. 2006 Jun;38(6):363-73
16631422
J Hepatol. 2007 May;46(5):858-68
17275124
Clin Liver Dis. 2007 Aug;11(3):577-96, vii
17723921
Gastroenterology. 2000 Feb;118(2):422-30
10648470
Hepatology. 2004 May;39(5):1267-76
15122755
Hepatology. 2004 Jun;39(6):1603-12
15185301
Toxicol Sci. 2001 Jan;59(1):169-77
11134556
Pharmacogenomics. 2008 Mar;9(3):359-63
18303971
Biochem Biophys Res Commun. 1996 Sep 24;226(3):695-702
8831677
Drug Metab Dispos. 2007 Oct;35(10):1963-9
17627974
Hepatology. 2006 Jul;44(1):27-33
16799979
Toxicology. 2008 Apr 3;246(1):24-33
18083283
J Hepatol. 2007 Oct;47(4):521-6
17692989
Nat Rev Drug Discov. 2005 Jun;4(6):489-99
15931258
J Toxicol Clin Toxicol. 1996;34(3):301-5
8667468
Expert Opin Drug Metab Toxicol. 2006 Aug;2(4):493-503
16859400
World J Gastroenterol. 2008 Jan 7;14(1):38-45
18176959
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4611-6
11287661
Hepatology. 1999 Feb;29(2):451-63
9918922
Hepatology. 2003 Apr;37(4):924-30
12668988
Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G583-9
16537970
Gut. 2007 Jul;56(7):982-90
17185352
Clin Pharmacol Ther. 2000 Apr;67(4):432-7
10801254