Molecular mechanisms underlying chemical liver injury

Xinsheng Gu; Jose E. Manautou

doi:10.1017/S1462399411002110

Molecular mechanisms underlying chemical liver injury

Published online by Cambridge University Press: 03 February 2012

Xinsheng Gu and

Jose E. Manautou

Show author details

Xinsheng Gu: Affiliation:
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
Jose E. Manautou*: Affiliation:
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
*: *Corresponding author: Jose E. Manautou, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269, USA. E-mail: [email protected]

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e4

DOI: https://doi.org/10.1017/S1462399411002110 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Nemeth, E., Baird, A.W. and O'Farrelly, C. (2009) Microanatomy of the liver immune system. Seminars in Immunopathology 31, 333-343CrossRef Google Scholar PubMed

2Dienes, H.P. and Drebber, U. (2010) Pathology of immune-mediated liver injury. Digestive Diseases 28, 57-62CrossRef Google Scholar PubMed

3Misdraji, J. (2010) Embryology, anatomy, histology, and developmental anomalies of the liver. In Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management (9th edn) (Sleisenger, M.H.Feldman, M. et al. , eds), pp. 1201-1206, Saunders/Elsevier, Philadelphia, PACrossRef Google Scholar

4Carithers, R.L. Jr. and Mcclain, C.J. (2010) Alcoholic liver disease. In Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management (9th edn) (Sleisenger, M.H.Feldman, M. et al. , eds), pp. 1383-1400, Saunders/Elsevier, Philadelphia, PACrossRef Google Scholar

5Jungermann, K. and Kietzmann, T. (1996) Zonation of parenchymal and nonparenchymal metabolism in liver. Annual Review of Nutrition 16, 179-203CrossRef Google Scholar PubMed

6Gebhardt, R. (1992) Metabolic zonation of the liver: regulation and implications for liver function. Pharmacology and Therapeutics 53, 275-354CrossRef Google Scholar PubMed

7Malarkey, D.E. et al. (2005) New insights into functional aspects of liver morphology. Toxicologic Pathology 33, 27-34CrossRef Google Scholar PubMed

8Gunawan, B. and Kaplowitz, N. (2004) Clinical perspectives on xenobiotic-induced hepatotoxicity. Drug Metabolism Reviews 36, 301-312CrossRef Google Scholar PubMed

9Henderson, N.C. and Iredale, J.P. (2007) Liver fibrosis: cellular mechanisms of progression and resolution. Clinical Science 112, 265-280CrossRef Google Scholar PubMed

10Guicciardi, M.E. and Gores, G.J. (2010) Apoptosis as a mechanism for liver disease progression. Seminars in Liver Disease 30, 402-410CrossRef Google Scholar PubMed

11Hochstein, C., Arnesen, S. and Goshorn, J. (2007) Environmental health and toxicology resources of the United States National Library of Medicine. Medical Reference Services Quarterly 26, 21-45CrossRef Google Scholar

12Kensler, T.W. et al. (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicological Sciences 120 (Suppl 1), S28-S48CrossRef Google Scholar PubMed

13Stubbs, M.A. and Morgan, M.Y. (2011) Managing alcohol dependence and alcohol-related liver disease: a problem for the hepatologist, psychiatrist or economist? Clinical Medicine 11, 189-193CrossRef Google Scholar PubMed

14Zimmerman, H.J. (1999) Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver (2nd edn), Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar

15Goldkind, L. and Laine, L. (2006) A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiology and Drug Safety 15, 213-220CrossRef Google Scholar PubMed

16Reuben, A., Koch, D.G. and Lee, W.M. (2010) Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 52, 2065-2076CrossRef Google Scholar

17Chun, L.J. et al. (2009) Acetaminophen hepatotoxicity and acute liver failure. Journal of Clinical Gastroenterology 43, 342-349CrossRef Google Scholar PubMed

18Rhee, S.M., Garg, V.K. and Hershey, C.O. (2004) Use of complementary and alternative medicines by ambulatory patients. Archives of Internal Medicine 164, 1004-1009CrossRef Google Scholar PubMed

19Seeff, L.B. (2007) Herbal hepatotoxicity. Clinics in Liver Disease 11, 577-596, viiCrossRef Google Scholar PubMed

20Lehman-McKeeman, L.D. (2008) Absorption, distribution, and excretion of toxicants. In Casarett and Doull's Toxicology: The Basic Science of Poisons (7th edn) (Casarett, L.J. and Doull, J. et al. , eds), pp. 131-159, McGraw-Hill, New YorkGoogle Scholar

21Parkinson, A. and Ogilvie, B.W. (2008) Biotransformation of xenobiotics. In Casarett and Doull's Toxicology: The Basic Science of Poisons (7th edn) (Casarett, L.J. and Doull, J. et al. , eds), pp. 161-304, McGraw-Hill, New YorkGoogle Scholar

22Testa, B. and Kramer, S.D. (2007) The biochemistry of drug metabolism – an introduction: part 3. Reactions of hydrolysis and their enzymes. Chemistry and Biodiversity 4, 2031-2122CrossRef Google Scholar PubMed

23Testa, B. and Kramer, S.D. (2007) The biochemistry of drug metabolism – an introduction: part 2. Redox reactions and their enzymes. Chemistry and Biodiversity 4, 257-405CrossRef Google Scholar PubMed

24Testa, B. and Kramer, S.D. (2008) The biochemistry of drug metabolism – an introduction: part 4. Reactions of conjugation and their enzymes. Chemistry and Biodiversity 5, 2171-2336CrossRef Google Scholar PubMed

25Trauner, M. and Boyer, J.L. (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiological Reviews 83, 633-671CrossRef Google Scholar PubMed

26Alrefai, W.A. and Gill, R.K. (2007) Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharmaceutical Research 24, 1803-1823CrossRef Google Scholar PubMed

27Kosters, A. and Karpen, S.J. (2008) Bile acid transporters in health and disease. Xenobiotica 38, 1043-1071CrossRef Google Scholar PubMed

28Nies, A.T., Schwab, M. and Keppler, D. (2008) Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opinion on Drug Metabolism and Toxicology 4, 545-568CrossRef Google Scholar PubMed

29Pang, K.S., Maeng, H.J. and Fan, J. (2009) Interplay of transporters and enzymes in drug and metabolite processing. Molecular Pharmaceutics 6, 1734-1755CrossRef Google Scholar PubMed

30Zamek-Gliszczynski, M.J. et al. (2006) Integration of hepatic drug transporters and phase II metabolizing enzymes: mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. European Journal of Pharmaceutical Sciences 27, 447-486CrossRef Google Scholar PubMed

31Williams, D.P. and Naisbitt, D.J. (2002) Toxicophores: groups and metabolic routes associated with increased safety risk. Current Opinion in Drug Discovery and Development 5, 104-115Google Scholar PubMed

32Kalgutkar, A.S. et al. (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Current Drug Metabolism 6, 161-225CrossRef Google Scholar PubMed

33Gregus, Z. (2008) Mechenism of toxicity. In Casarett and Doull's Toxicology: The Basic Science of Poisons (7th edn) (Casarett, L.J. and Doull, J. et al. , eds), pp. 45-106, McGraw-Hill, New YorkGoogle Scholar

34Testa, B. and Kramer, S.D. (2009) The biochemistry of drug metabolism – an introduction: part 5. Metabolism and bioactivity. Chemistry and Biodiversity 6, 591-684CrossRef Google Scholar PubMed

35Mason, R.P. and Chignell, C.F. (1981) Free radicals in pharmacology and toxicology – selected topics. Pharmacological Reviews 33, 189-211Google Scholar PubMed

36Mason, R.P. (1982) Free radical intermediates in the metabolism of toxic chemicals. In Free Radicals in Biology (vol. 5) (Pryor, W.A., ed.), pp. 161-222, Academic Press, New YorkCrossRef Google Scholar

37Valko, M., Morris, H. and Cronin, M.T. (2005) Metals, toxicity and oxidative stress. Current Medicinal Chemistry 12, 1161-1208CrossRef Google Scholar PubMed

38Aust, S.D. et al. (1993) Free radicals in toxicology. Toxicology and Applied Pharmacology 120, 168-178CrossRef Google Scholar PubMed

39Halliwell, B. and Cross, C.E. (1994) Oxygen-derived species: their relation to human disease and environmental stress. Environmental Health Perspectives 102 (Suppl 10), 5-12Google Scholar PubMed

40Ferrer-Sueta, G. and Radi, R. (2009) Chemical biology of peroxynitrite: kinetics, diffusion, and radicals. ACS Chemical Biology 4, 161-177CrossRef Google Scholar PubMed

41Gutteridge, J.M. (1994) Biological origin of free radicals, and mechanisms of antioxidant protection. Chemico-biological Interactions 91, 133-140CrossRef Google Scholar PubMed

42Circu, M.L. and Aw, T.Y. (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radical Biology and Medicine 48, 749-762CrossRef Google Scholar PubMed

43Zangar, R.C., Davydov, D.R. and Verma, S. (2004) Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicology and Applied Pharmacology 199, 316-331CrossRef Google Scholar PubMed

44Kovacic, P. et al. (2005) Mechanism of mitochondrial uncouplers, inhibitors, and toxins: focus on electron transfer, free radicals, and structure–activity relationships. Current Medicinal Chemistry 12, 2601-2623CrossRef Google Scholar PubMed

45Murphy, M.P. (2009) How mitochondria produce reactive oxygen species. Biochemical Journal 417, 1-13CrossRef Google Scholar PubMed

46Fritz, R. et al. (2007) Compartment-dependent management of H(2)O(2) by peroxisomes. Free Radical Biology and Medicine 42, 1119-1129CrossRef Google Scholar

47Davies, K.J. (2000) Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB Life 50, 279-289CrossRef Google Scholar PubMed

48Williams, D.P. et al. (2002) Are chemically reactive metabolites responsible for adverse reactions to drugs? Current Drug Metabolism 3, 351-366CrossRef Google Scholar PubMed

49McCarver, D.G. and Hines, R.N. (2002) The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. Journal of Pharmacology and Experimental Therapeutics 300, 361-366CrossRef Google Scholar PubMed

50van Bladeren, P.J. (2000) Glutathione conjugation as a bioactivation reaction. Chemico-Biological Interactions 129, 61-76CrossRef Google Scholar PubMed

51Whalen, R. and Boyer, T.D. (1998) Human glutathione S-transferases. Seminars in Liver Disease 18, 345-358CrossRef Google Scholar PubMed

52Dragovic, S. et al. (2010) Role of human glutathione S-transferases in the inactivation of reactive metabolites of clozapine. Chemical Research in Toxicology 23, 1467-1476CrossRef Google Scholar PubMed

53Forman, H.J., Zhang, H. and Rinna, A. (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Molecular Aspects of Medicine 30, 1-12CrossRef Google Scholar PubMed

54Lu, S.C. (2009) Regulation of glutathione synthesis. Molecular Aspects of Medicine 30, 42-59CrossRef Google Scholar PubMed

55Hansen, J.M., Go, Y.M. and Jones, D.P. (2006) Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annual Review of Pharmacology and Toxicology 46, 215-234CrossRef Google Scholar PubMed

56Jones, D.P. (2006) Redefining oxidative stress. Antioxidants and Redox Signaling 8, 1865-1879CrossRef Google Scholar PubMed

57Circu, M.L. and Aw, T.Y. (2008) Glutathione and apoptosis. Free Radical Research 42, 689-706CrossRef Google Scholar PubMed

58Yuan, L. and Kaplowitz, N. (2009) Glutathione in liver diseases and hepatotoxicity. Molecular Aspects of Medicine 30, 29-41CrossRef Google Scholar PubMed

59Han, D. et al. (2006) Mechanisms of liver injury. III. Role of glutathione redox status in liver injury. American Journal of Physiology. Gastrointestinal and Liver Physiology 291, G1-G7CrossRef Google Scholar PubMed

60Kaplowitz, N. (2000) Mechanisms of liver cell injury. Journal of Hepatology 32, 39-47CrossRef Google Scholar PubMed

61Biswas, S., Chida, A.S. and Rahman, I. (2006) Redox modifications of protein-thiols: emerging roles in cell signaling. Biochemical Pharmacology 71, 551-564CrossRef Google Scholar PubMed

62Kalinina, E.V., Chernov, N.N. and Saprin, A.N. (2008) Involvement of thio-, peroxi-, and glutaredoxins in cellular redox-dependent processes. Biochemistry 73, 1493-1510Google Scholar PubMed

63Srivastava, A. et al. (2010) Role of reactive metabolites in drug-induced hepatotoxicity. Handbook of Experimental Pharmacology 196, 165-194CrossRef Google Scholar

64Zhou, S. et al. (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metabolism Reviews 37, 41-213CrossRef Google Scholar PubMed

65Cohen, S.D. et al. (1997) Selective protein covalent binding and target organ toxicity. Toxicology and Applied Pharmacology 143, 1-12CrossRef Google Scholar PubMed

66Davern, T.J. 2nd, et al. (2006) Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 130, 687-694CrossRef Google Scholar PubMed

67James, L.P. et al. (2009) Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metabolism and Disposition 37, 1779-1784CrossRef Google Scholar PubMed

68Hanzlik, R.P. et al. (2007) The reactive metabolite target protein database (TPDB) – a web-accessible resource. BMC Bioinformatics 8, 95CrossRef Google Scholar PubMed

69Liebler, D.C. (2008) Protein damage by reactive electrophiles: targets and consequences. Chemical Research in Toxicology 21, 117-128CrossRef Google Scholar PubMed

70Thiele, G.M., Klassen, L.W. and Tuma, D.J. (2008) Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods in Molecular Biology 447, 235-257CrossRef Google Scholar PubMed

71Rubino, F.M. et al. (2009) Toward an ‘omic’ physiopathology of reactive chemicals: thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds. Mass Spectrometry Reviews 28, 725-784CrossRef Google Scholar PubMed

72Benigni, R. (2005) Structure-activity relationship studies of chemical mutagens and carcinogens: mechanistic investigations and prediction approaches. Chemical Reviews 105, 1767-1800CrossRef Google Scholar PubMed

73Kho, R. et al. (2005) Ring systems in mutagenicity databases. Journal of Medicinal Chemistry 48, 6671-6678CrossRef Google Scholar PubMed

74Dizdaroglu, M. et al. (2002) Free radical-induced damage to DNA: mechanisms and measurement. Free Radical Biology and Medicine 32, 1102-1115CrossRef Google Scholar PubMed

75Burcham, P.C. (1998) Genotoxic lipid peroxidation products: their DNA damaging properties and role in formation of endogenous DNA adducts. Mutagenesis 13, 287-305CrossRef Google Scholar PubMed

76Dix, T.A. and Aikens, J. (1993) Mechanisms and biological relevance of lipid peroxidation initiation. Chemical Research in Toxicology 6, 2-18CrossRef Google Scholar PubMed

77Poli, G., Biasi, F. and Leonarduzzi, G. (2008) 4-Hydroxynonenal-protein adducts: a reliable biomarker of lipid oxidation in liver diseases. Molecular Aspects of Medicine 29, 67-71CrossRef Google Scholar PubMed

78Smathers, R.L. et al. (2011) Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease. Chemico-biological Interactions 192, 107-112CrossRef Google Scholar PubMed

79Poli, G., Albano, E. and Dianzani, M.U. (1987) The role of lipid peroxidation in liver damage. Chemistry and Physics of Lipids 45, 117-142CrossRef Google Scholar PubMed

80Ghezzi, P., Bonetto, V. and Fratelli, M. (2005) Thiol-disulfide balance: from the concept of oxidative stress to that of redox regulation. Antioxidants and Redox Signaling 7, 964-972CrossRef Google Scholar PubMed

81Gallogly, M.M. and Mieyal, J.J. (2007) Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress. Current Opinion in Pharmacology 7, 381-391CrossRef Google Scholar PubMed

82Schafer, F.Q. and Buettner, G.R. (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology and Medicine 30, 1191-1212CrossRef Google Scholar PubMed

83Farout, L. and Friguet, B. (2006) Proteasome function in aging and oxidative stress: implications in protein maintenance failure. Antioxidants and Redox Signaling 8, 205-216CrossRef Google Scholar PubMed

84Klatt, P. and Lamas, S. (2000) Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. European Journal of Biochemistry 267, 4928-4944CrossRef Google Scholar PubMed

85Farber, J.L. (1994) Mechanisms of cell injury by activated oxygen species. Environmental Health Perspectives 102 (Suppl 10), 17-24Google Scholar PubMed

86Turrens, J.F. (1997) Superoxide production by the mitochondrial respiratory chain. Bioscience Reports 17, 3-8CrossRef Google Scholar PubMed

87Smathers, R.L. et al. (2011) Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease. Chemico-biological Interactions 192, 107-112CrossRef Google Scholar PubMed

88Valerio, L.G. Jr and Petersen, D.R. (1998) Formation of liver microsomal MDA-protein adducts in mice with chronic dietary iron overload. Toxicology Letters 98, 31-39CrossRef Google Scholar PubMed

89Rudolph, T.K. and Freeman, B.A. (2009) Transduction of redox signaling by electrophile-protein reactions. Science Signaling 2, re7CrossRef Google Scholar PubMed

90Beddowes, E.J., Faux, S.P. and Chipman, J.K. (2003) Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress. Toxicology 187, 101-115CrossRef Google Scholar PubMed

91Czaja, M.J. (2007) Cell signaling in oxidative stress-induced liver injury. Seminars in Liver Disease 27, 378-389CrossRef Google Scholar PubMed

92Allen, R.G. and Tresini, M. (2000) Oxidative stress and gene regulation. Free Radical Biology and Medicine 28, 463-499CrossRef Google Scholar PubMed

93Zima, T. and Kalousova, M. (2005) Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcoholism, Clinical and Experimental Research 29, 110S-115SCrossRef Google Scholar PubMed

94Wu, D. and Cederbaum, A.I. (2009) Oxidative stress and alcoholic liver disease. Seminars in Liver Disease 29, 141-154CrossRef Google Scholar PubMed

95Ugarte, N., Petropoulos, I. and Friguet, B. (2010) Oxidized mitochondrial protein degradation and repair in aging and oxidative stress. Antioxidants and Redox Signaling 13, 539-549CrossRef Google Scholar PubMed

96Lee, S. and Tsai, F.T. (2005) Molecular chaperones in protein quality control. Journal of Biochemistry and Molecular Biology 38, 259-265Google Scholar PubMed

97Zhang, Y. et al. (2010) Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. Antioxidants and Redox Signaling 13, 999-1009CrossRef Google Scholar PubMed

98Breusing, N. and Grune, T. (2008) Regulation of proteasome-mediated protein degradation during oxidative stress and aging. Biological Chemistry 389, 203-209CrossRef Google Scholar PubMed

99Christmann, M. et al. (2003) Mechanisms of human DNA repair: an update. Toxicology 193, 3-34CrossRef Google Scholar PubMed

100Camenisch, U. and Naegeli, H. (2009) Role of DNA repair in the protection against genotoxic stress. Exs 99, 111-150Google Scholar PubMed

101Ciccia, A. and Elledge, S.J. (2010) The DNA damage response: making it safe to play with knives. Molecular Cell 40, 179-204CrossRef Google Scholar PubMed

102Barouki, R. (2010) Linking long-term toxicity of xeno-chemicals with short-term biological adaptation. Biochimie 92, 1222-1226CrossRef Google Scholar PubMed

103Xie, W. et al. (2004) Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism. Drug Discovery Today 9, 442-449CrossRef Google Scholar PubMed

104Ramadoss, P., Marcus, C. and Perdew, G.H. (2005) Role of the aryl hydrocarbon receptor in drug metabolism. Expert Opinion on Drug Metabolism and Toxicology 1, 9-21CrossRef Google Scholar PubMed

105Copple, I.M. et al. (2010) The keap1-nrf2 cellular defense pathway: mechanisms of regulation and role in protection against drug-induced toxicity. Handbook of Experimental Pharmacology 196, 233-266CrossRef Google Scholar

106Shen, G. and Kong, A.N. (2009) Nrf2 plays an important role in coordinated regulation of phase II drug metabolism enzymes and phase III drug transporters. Biopharmaceutics and Drug Disposition 30, 345-355CrossRef Google Scholar PubMed

107Williams, G.M. and Iatropoulos, M.J. (2002) Alteration of liver cell function and proliferation: differentiation between adaptation and toxicity. Toxicologic Pathology 30, 41-53CrossRef Google Scholar PubMed

108Green, D.R. and Kroemer, G. (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127-1130CrossRef Google Scholar PubMed

109Orrenius, S., Nicotera, P. and Zhivotovsky, B. (2011) Cell death mechanisms and their implications in toxicology. Toxicological Sciences 119, 3-19CrossRef Google Scholar PubMed

110Pessayre, D. et al. (2010) Mitochondrial involvement in drug-induced liver injury. Handbook of Experimental Pharmacology 196, 311-365CrossRef Google Scholar

111Jones, D.P. et al. (2010) Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Molecular Interventions 10, 98-111CrossRef Google Scholar PubMed

112Kass, G.E. (2006) Mitochondrial involvement in drug-induced hepatic injury. Chemico-biological Interactions 163, 145-159CrossRef Google Scholar PubMed

113Malhi, H., Guicciardi, M.E. and Gores, G.J. (2010) Hepatocyte death: a clear and present danger. Physiological Reviews 90, 1165-1194CrossRef Google Scholar

114Wei, M.C. et al. (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727-730CrossRef Google Scholar

115Joza, N. et al. (2001) Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410, 549-554CrossRef Google Scholar PubMed

116Jones, B.E. et al. (2000) Hepatocytes sensitized to tumor necrosis factor-alpha cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways. Journal of Biological Chemistry 275, 705-712CrossRef Google Scholar PubMed

117Lemasters, J.J. (1999) V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. American Journal of Physiology 276, G1-G6Google Scholar PubMed

118Nagy, L.E. (2003) Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Experimental Biology and Medicine (Maywood, NJ) 228, 882-890CrossRef Google Scholar PubMed

119Nath, B. and Szabo, G. (2009) Alcohol-induced modulation of signaling pathways in liver parenchymal and nonparenchymal cells: implications for immunity. Seminars in Liver Disease 29, 166-177CrossRef Google Scholar PubMed

120Depta, J.P. et al. (2004) Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity. Journal of Allergy and Clinical Immunology 113, 519-527CrossRef Google Scholar PubMed

121Kaplowitz, N. (2002) Biochemical and cellular mechanisms of toxic liver injury. Seminars in Liver Disease 22, 137-144CrossRef Google Scholar PubMed

122Holt, M.P. and Ju, C. (2006) Mechanisms of drug-induced liver injury. AAPS Journal 8, E48-E54CrossRef Google Scholar PubMed

123Ju, C. and Uetrecht, J.P. (2002) Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Current Drug Metabolism 3, 367-377CrossRef Google Scholar PubMed

124Adams, D.H. et al. (2010) Mechanisms of immune-mediated liver injury. Toxicological Sciences 115, 307-321CrossRef Google Scholar PubMed

125Pauli-Magnus, C. and Meier, P.J. (2006) Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778-787CrossRef Google Scholar PubMed

126Kosters, A. and Karpen, S.J. (2010) The role of inflammation in cholestasis: clinical and basic aspects. Seminars in Liver Disease 30, 186-194CrossRef Google Scholar

127Geier, A. et al. (2007) Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochimica et Biophysica Acta 1773, 283-308CrossRef Google Scholar PubMed

128Pauli-Magnus, C., Meier, P.J. and Stieger, B. (2010) Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Seminars in Liver Disease 30, 147-159CrossRef Google Scholar PubMed

129Kaplowitz, N. (2005) Idiosyncratic drug hepatotoxicity. Nature Reviews. Drug Discovery 4, 489-499CrossRef Google Scholar PubMed

130Zhang, X. et al. (2011) Involvement of the immune system in idiosyncratic drug reactions. Drug Metabolism and Pharmacokinetics 26, 47-59Google Scholar PubMed

131Uetrecht, J. (2008) Idiosyncratic drug reactions: past, present, and future. Chemical Research in Toxicology 21, 84-92CrossRef Google Scholar PubMed

132Li, J. and Uetrecht, J.P. (2010) The danger hypothesis applied to idiosyncratic drug reactions. Handbook of Experimental Pharmacology 196, 493-509CrossRef Google Scholar

133Daly, A.K. (2010) Drug-induced liver injury: past, present and future. Pharmacogenomics 11, 607-611CrossRef Google Scholar PubMed

134Smith, D.A. and Obach, R.S. (2009) Metabolites in safety testing (MIST): considerations of mechanisms of toxicity with dose, abundance, and duration of treatment. Chemical Research in Toxicology 22, 267-279CrossRef Google Scholar PubMed

135Uetrecht, J.P. (1999) New concepts in immunology relevant to idiosyncratic drug reactions: the ‘danger hypothesis’ and innate immune system. Chemical Research in Toxicology 12, 387-395CrossRef Google Scholar PubMed

136Zhou, S.F. (2008) Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Current Drug Metabolism 9, 310-322CrossRef Google Scholar PubMed

137Nelson, D.R. (2009) The cytochrome p450 homepage. Human Genomics 4, 59-65CrossRef Google Scholar PubMed

138Martinez-Jimenez, C.P. et al. (2007) Transcriptional regulation and expression of CYP3A4 in hepatocytes. Current Drug Metabolism 8, 185-194CrossRef Google Scholar PubMed

139Liu, Y. et al. (2009) The effects of splicing variant of PXR PAR-2 on CYP3A4 and MDR1 mRNA expressions. Clinica Chimica Acta 403, 142-144CrossRef Google Scholar PubMed

140Koyano, S. et al. (2004) Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region. Drug Metabolism and Disposition 32, 149-154CrossRef Google Scholar PubMed

141Tompkins, L.M., Sit, T.L. and Wallace, A.D. (2008) Unique transcription start sites and distinct promoter regions differentiate the pregnane X receptor (PXR) isoforms PXR 1 and PXR 2. Drug Metabolism and Disposition 36, 923-929CrossRef Google Scholar PubMed

142Ingelman-Sundberg, M. (2005) The human genome project and novel aspects of cytochrome P450 research. Toxicology and Applied Pharmacology 207, 52-56CrossRef Google Scholar PubMed

143Zanger, U.M. et al. (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and Bioanalytical Chemistry 392, 1093-1108CrossRef Google Scholar PubMed

144Sim, S.C. and Ingelman-Sundberg, M. (2010) The human cytochrome P450 (CYP) allele nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Human Genomics 4, 278-281CrossRef Google Scholar PubMed

145Correia, M.A., Sinclair, P.R. and De Matteis, F. (2011) Cytochrome P450 regulation: the interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal. Drug Metabolism Reviews 43, 1-26CrossRef Google Scholar PubMed

146Hernandez, J.P., Mota, L.C. and Baldwin, W.S. (2009) Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation. Current Pharmacogenomics and Personalized Medicine 7, 81-105CrossRef Google Scholar PubMed

147Zollner, G. et al. (2006) Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Molecular Pharmaceutics 3, 231-251CrossRef Google Scholar PubMed

148Lynch, T. and Price, A. (2007) The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. American Family Physician 76, 391-396Google Scholar PubMed

149Pelkonen, O. et al. (2008) Inhibition and induction of human cytochrome P450 enzymes: current status. Archives of Toxicology 82, 667-715CrossRef Google Scholar PubMed

150Hakkola, J., Tanaka, E. and Pelkonen, O. (1998) Developmental expression of cytochrome P450 enzymes in human liver. Pharmacology and Toxicology 82, 209-217CrossRef Google Scholar PubMed

151Hines, R.N. (2007) Ontogeny of human hepatic cytochromes P450. Journal of Biochemical and Molecular Toxicology 21, 169-175CrossRef Google Scholar PubMed

152Wolbold, R. et al. (2003) Sex is a major determinant of CYP3A4 expression in human liver. Hepatology 38, 978-988CrossRef Google Scholar

153Daly, A.K. et al. (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics 41, 816-819CrossRef Google Scholar

154Evans, D.C. et al. (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chemical Research in Toxicology 17, 3-16CrossRef Google Scholar PubMed

155Coles, B. (1984) Effects of modifying structure on electrophilic reactions with biological nucleophiles. Drug Metabolism Reviews 15, 1307-1334CrossRef Google Scholar PubMed

156Kalgutkar, A.S. (2011) Handling reactive metabolite positives in drug discovery: what has retrospective structure-toxicity analyses taught us? Chemico-biological Interactions 192, 46-55CrossRef Google Scholar PubMed

157Thompson, R.A. et al. (2011) Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chemico-biological Interactions 192, 65-71CrossRef Google Scholar PubMed

158Halegoua-De Marzio, D. and Navarro, V.J. (2008) Drug-induced hepatotoxicity in humans. Current Opinion in Drug Discovery and Development 11, 53-59Google Scholar PubMed

159Chang, L.W. et al. (1994) Macromolecular adducts: biomarkers for toxicity and carcinogenesis. Annual Review of Pharmacology and Toxicology 34, 41-67CrossRef Google Scholar PubMed

160Consortium, T.I.H. (2005) A haplotype map of the human genome. Nature 437, 1299-1320CrossRef Google Scholar

161Durbin, R.M. et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467, 1061-1073Google Scholar

162Birney, E. et al. (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799-816Google Scholar PubMed

Article contents

Molecular mechanisms underlying chemical liver injury

Abstract

Access options

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

Molecular mechanisms underlying chemical liver injury

Abstract

Access options

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests