The role of metabolic activation in drug-induced hepatotoxicity

Annual Review of Pharmacology and Toxicology

Volumn 45, Issue , 2005, Pages 177-202

  Park, B Kevin ^a   Kitteringham, Neil R ^a   Maggs, James L ^a   Pirmohamed, Munir ^a   Williams, Dominic P ^a  

^a UNIVERSITY OF LIVERPOOL   (United Kingdom)

Author keywords

Acetaminophen; Bioactivation; Chemically reactive metabolite; Critical protein; Diclofenac; Tamoxifen; Troglitazone

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ANTIDIABETIC AGENT; CARBAMAZEPINE; DICLOFENAC; DIHYDRALAZINE; HALOTHANE; ISONIAZID; NEVIRAPINE; PARACETAMOL; PIOGLITAZONE; ROSIGLITAZONE; SULFAMETHOXAZOLE; TAMOXIFEN; TIENILIC ACID; TROGLITAZONE;

CHEMICAL CARCINOGENESIS; COVALENT BOND; DRUG INDUCED DISEASE; HUMAN; LIVER TOXICITY; METABOLIC ACTIVATION; METABOLITE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN MODIFICATION; PROTEIN TARGETING; QUANTITATIVE DIAGNOSIS; REACTION ANALYSIS; REVIEW; STRUCTURE ACTIVITY RELATION; TECHNOLOGY; TISSUE INJURY;

ANIMALS; BIOTRANSFORMATION; HEPATITIS, TOXIC; HUMANS; LIVER; PHARMACEUTICAL PREPARATIONS;

EID: 13844314221     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.45.120403.100058     Document Type: Review

References (98)

1. Lee WM. 2003. Drug-induced hepatotoxicity. New Engl. J. Med. 349:474-85
2. Miller E, Miller J. 1947. The presence and significance of bound aminoazo dyes in the livers of rats fed p-dimethyl-aminobenzene. Cancer Res. 7:468-80
3. Miller E, Miller J. 1952. In vivo combinations between carcinogens and tissue constituents and their possible role in carcinogenesis. Cancer Res. 12:547-56
4. Brodie BB, Reid WD, Cho AK, Sipes G, Krishna G, Gillette JR. 1971. Possible mechanism of liver necrosis caused by aromatic organic compounds. Proc. Natl. Acad. Sci. USA 68:160-64
5. Gillette JR, Mitchell JR, Brodie BB. 1974. Biochemical mechanisms of drug toxicity. Annu. Rev. Pharmacol. 14:271-88
6. Tirmenstein MA, Nelson SD. 1989. Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J. Biol. Chem. 264:9814-19
7. Kawamoto Y, Nakamura Y, Naito Y, Torii Y, Kumagai T, et al. 2000. Cyclopentenone prostaglandins as potential inducers of phase II detoxification enzymes. 15-deoxy-delta(12,14)-prostaglandin j2-induced expression of glutathione S-transferases. J. Biol. Chem. 275:11291-99
8. Guengerich FP, Johnson WW, Ueng YF, Yamazaki H, Shimada T. 1996. Involvement of cytochrome P450, glutathione S-transferase, and epoxide hydrolase in the metabolism of aflatoxin B1 and relevance to risk of human liver cancer. Environ. Health Perspect. 104(Suppl. 3): 557-62
9. Wilson AS, Williams DP, Davis CD, Tingle MD, Park BK. 1997. Bioactivation and inactivation of aflatoxin B1 by human, mouse and rat liver preparations: effect on SCE in human mononuclear leucocytes. Mutat. Res. 373:257-64
10. Gonzalez FJ, Kimura S. 1999. Role of gene knockout mice in understanding the mechanisms of chemical toxicity and carcinogenesis. Cancer Lett. 143:199-204
11. Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR. 1998. Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc. Natl. Acad. Sci. USA 95:5275-80
12. Carthew P, Rich KJ, Martin EA, De Matteis F, Lim CK, et al. 1995. DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation. Carcinogenesis 16:1299-304
13. Group EBCTC. 1998. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451-67
14. Martin EA, Rich KJ, White IN, Woods KL, Powles TJ, Smith LL. 1995. 32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis 16:1651-54
15. Boocock DJ, Maggs JL, White IN, Park BK. 1999. Alpha-hydroxytamoxifen, a genotoxic metabolite of tamoxifen in the rat: identification and quantification in vivo and in vitro. Carcinogenesis 20:153-60
16. Boocock DJ, Maggs JL, Brown K, White INH, Park BK. 2000. Major inter-species differences in the rates of O-sulphonation and O-glucuronylation of alpha-hydroxytamoxifen in vitro: a metabolic disparity protecting human liver from the formation of tamoxifen-DNA adducts. Carcinogenesis 21:1851-58
17. Raucy JL, Lasker JM, Lieber CS, Black M. 1989. Acetaminophen activation by human liver cytochromes P450-IIE1 and P450IA2. Arch. Biochem. Biophys. 271:270-83
18. Thummel KE, Lee CA, Kunze KL, Nelson SD, Slattery JT. 1993. Oxidation of acetaminophen to N-acetyl-p-amino-benzoquinone imine by human CYP3A4. Biochem. Pharmacol 45:1563-69
19. Davis DC, Potter WZ, Jollow DJ, Mitchell JR. 1974. Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci. 14:2099-109
20. Albano E, Rundgren M, Harvison PJ, Nelson SD, Moldeus P. 1985. Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol. Pharmacol. 28:306-11
21. Rafeiro E, Barr SG, Harrison JJ, Racz WJ. 1994. Effects of N-acetylcysteine and dithiothreitol on glutathione and protein thiol replenishment during acetaminophen-induced toxicity in isolated mouse hepatocytes. Toxicology 93:209-24
22. Goldring C, Kitteringham N, Elsby R, Randle L, Clement Y, et al. 2004. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology 39:1267-76
23. Kitteringham NR, Powell H, Clement YN, Dodd CC, Tettey JN, et al. 2000. Hepatocellular response to chemical stress in CD-1 mice: induction of early genes and gamma-glutamylcysteine synthetase. Hepatology 32:321-33
24. Dietze EC, Schafer A, Omichinski JG, Nelson SD. 1997. Inactivation of glyceraldehyde-3-phosphate dehydrogenase by a reactive metabolite of acetaminophen and mass spectral characterization of an arylated active site peptide. Chem. Res. Toxicol. 10:1097-103
25. Zhou L, McKenzie BA, Eccleston ED Jr, Srivastava SP, Chen N, et al. 1996. The covalent binding of [14C] acetaminophen to mouse hepatic microsomal proteins: the specific binding to calreticulin and the two forms of the thiol:protein disulfide oxidoreductases. Chem. Res. Toxicol. 9:1176-82
26. Andersson BS, Rundgren M, Nelson SD, Harder S. 1990. N-acetyl-p- benzoquinone imine-induced changes in the energy metabolism in hepatocytes. Chem. Biol. Interact. 75:201-11
27. Burcham PC, Harman AW. 1991. Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J. Biol. Chem. 266:5049-54
28. Karbowski M, Kurono C, Wozniak M, Ostrowski M, Teranishi M, et al. 1999. Free radical-induced megamitochondria formation and apoptosis. Free Radic. Biol. Med. 26:396-409
29. Goldin RD, Ratnayaka ID, Breach CS, Brown IN, Wickramasinghe SN. 1996. Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J. Pathol. 179:432-35
30. Laskin DL, Pilaro AM. 1986. Potential role of activated macrophages in acetaminophen hepatotoxicity. I. Isolation and characterization of activated macrophages from rat liver. Toxicol. Appl. Pharmacol. 86:204-15
31. Zhang H, Cook J, Nickel J, Yu R, Stecker K, et al. 2000. Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis. Nat. Biotechnol. 18:862-67
32. Blazka ME, Elwell MR, Holladay SD, Wilson RE, Luster MI. 1996. Histopathology of acetaminophen-induced liver changes-role of interleukin-1-alpha and tumor-necrosis-factor-alpha. Toxicol. Pathol. 24:181-89
33. Ito Y, Abril ER, Bethea NW, McCuskey RS. 2004. Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 286:G60-67
34. Kenna JG. 1997. Immunoallergic drug-induced hepatitis: lessons from halothane. J. Hepatol. 26(Suppl. 1):5-12
35. Vergani D, Mieli-Vergani G, Alberti A, Neuberger J, Eddleston AL, et al. 1980. Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. New Engl. J. Med. 303:66-71
36. Martin JL, Kenna JG, Martin BM, Thomassen D, Reed GF, Pohl LR. 1993. Halothane hepatitis patients have serum antibodies that react with protein disulfide isomerase. Hepatology 18:858-63
37. Martin JL, Pumford NR, LaRosa AC, Martin BM, Gonzaga HM, et al. 1991. A metabolite of halothane covalently binds to an endoplasmic reticulum protein that is highly homologous to phosphatidylinositol-specific phospholipase C-alpha but has no activity. Biochem. Biophys. Res. Commun. 178:679-85
38. Hayden PJ, Ichimura T, McCann DJ, Pohl LR, Stevens JL. 1991. Detection of cysteine conjugate metabolite adduct formation with specific mitochondrial proteins using antibodies raised against halothane metabolite adducts. J. Biol. Chem. 266:18415-18
39. Bourdi M, Chen W, Peter RM, Martin JL, Buters JT, et al. 1996. Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem. Res. Toxicol. 9:1159-66
40. Lohse AW, Manns M, Dienes HP, Meyer zum Buschenfelde KH, Cohen IR. 1990. Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity. Hepatology 11:24-30
41. Lohse AW, Brunner S, Kyriatsoulis A, Manns M, Meyer zum Buschenfelde KH. 1992. Autoantibodies in experimental autoimmune hepatitis. J. Hepatol. 14:48-53
42. Lecoeur S, Andre C, Beaune PH. 1996. Tienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol. Pharmacol. 50:326-33
43. Eliasson E, Kenna JG. 1996. Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol. Pharmacol. 50:573-82
44. Belloc C, Gauffre A, Andre C, Beaune PH. 1997. Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis. Pharmacogenetics 7:181-86
45. Kitteringham NR, Kenna JG, Park BK. 1995. Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane-associated hepatitis. Br. J. Clin. Pharmacol. 40:379-86
46. Naisbitt DJ, Britschgi M, Wong G, Farrell J, Depta JP, et al. 2003. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol. Pharmacol 63:732-41
47. Mitchell JR, Zimmerman HJ, Ishak KG, Thorgeirsson UP, Timbrell JA, et al. 1976. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann. Intern. Med. 84:181-92
48. Zimmerman HJ. 1990. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroidal drugs, anti-inflammatory drugs, antibiotics, antihypertensives, and cardiac and psychotropic agents. Semin. Liver Dis. 10:322-38
49. Zimmerman HJ, Ishak KG. 1995. Morphologic spectrum of drug-induced hepatic disease. Gastroenterol. Clin. North Am. 24:759-86
50. Durand F, Bernuau J, Pessayre D, Samuel D, Belaiche J, et al. 1995. Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculous treatment including isoniazid. Hepatology 21:929-32
51. Ormerod LP, Skinner C, Wales J. 1996. Hepatotoxicity of antituberculosis drugs. Thorax 51:111-13
52. Schaberg T, Rebhan K, Lode H. 1996. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir. J. 9:2026-30
53. Nelson SD, Mitchell JR, Timbrell JA, Snodgrass WR, Corcoran GB 3rd. 1976. Isoniazid and iproniazid: activation of metabolites to toxic intermediates in man and rat. Science 193:901-3
54. Sarich TC, Zhou T, Adams SP, Bain AI, Wall RA, Wright JM. 1995. A model of isoniazid-induced hepatotoxicity in rabbits. J. Pharmacol. Toxicol. Methods 34:109-16
55. Rozwarski DA, Grant GA, Barton DH, Jacobs WR Jr, Sacchettini JC. 1998. Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279:98-102
56. Rawat R, Whitty A, Tonge PJ. 2003. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc. Natl. Acad. Sci. USA 100:13881-86
57. Fontana RJ, McCashland TM, Benner KG, Appelman HD, Gunartanam NT, et al. 1999. Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. The Acute Liver Failure Study Group. Liver Transpl. Surg. 5:480-84
58. Kenny JR, Maggs JL, Meng X, Sinnott D, Clarke SE, et al. 2004. Syntheses and characterisation of the acyl glucuronide and hydroxy metabolites of diclofenac. J. Med. Chem. 47:2816-25
59. Grillo MP, Hua F, Knutson CG, Ware JA, Li C. 2003. Mechanistic studies on the bioactivation of diclofenac: identification of diclofenac-S-acyl- glutathione in vitro in incubations with rat and human hepatocytes. Chem. Res. Toxicol. 16:1410-17
60. Shen S, Marchick MR, Davis MR, Doss GA, Pohl LR. 1999. Metabolic activation of diclofenac by human cytochrome P450 3A4: role of 5-hydroxydiclofenac. Chem. Res. Toxicol. 12:214-22
61. Tang W, Steams RA, Bandiera SM, Zhang Y, Raab C, et al. 1999. Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites. Drug Metab. Dispos. 27:365-72
62. Masubuchi Y, Ose A, Horie T. 2002. Diclofenac-induced inactivation of CYP3A4 and its stimulation by quinidine. Drug Metab. Dispos. 30:1143-48
63. Kretz-Rommel A, Boelsterli UA. 1993. Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes. Toxicol Appl. Pharmacol. 120:155-61
64. Boelsterli UA. 2003. Mechanistic Toxicology. Chapter 9:202. London: Taylor & Francis
65. Hargus SJ, Martin BM, George JW, Pohl LR. 1995. Covalent modification of rat liver dipeptidyl peptidase IV (CD26) by the nonsteroidal anti-inflammatory drug diclofenac. Chem. Res. Toxicol. 8:993-96
66. Tolman KG, Chandramouli J. 2003. Hepatotoxicity of the thiazolidinediones. Clin. Liver Dis. 7:369-79, vi
67. Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, et al. 2001. Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem. Res. Toxicol. 14:62-70
68. Tettey JN, Maggs JL, Rapeport WG, Pirmohamed M, Park BK. 2001. Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo. Chem. Res. Toxicol. 14:965-74
69. Satoh H, Dilone E, Nangia A, Zhao S, Frank K. 2000. Covalent adducts in human primary hepatocytes cultured with [14C]-troglitazone. Drug Metab. Rev. 32(Suppl. 2):204
70. Prabhu S, Fackett A, Lloyd S, McClellan HA, Terrell CM, et al. 2002. Identification of glutathione conjugates of troglitazone in human hepatocytes. Chem. Biol. Interact. 142:83-97
71. Haskins JR, Rowse P, Rahbari R, de la Iglesia FA. 2001. Thiazolidinedione toxicity to isolated hepatocytes revealed by coherent multiprobe fluorescence microscopy and correlated with multiparameter flow cytometry of peripheral leukocytes. Arch. Toxicol. 75:425-38
72. Watanabe I, Tomita A, Shimizu M, Sugawara M, Yasumo H, et al. 2003. A study to survey susceptible genetic factors responsible for troglitazone- associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 73:435-55
73. Jayyosi Z, Muc M, Gallagher M, Toutain H, Stevens J, Kelley M. 1999. Covalent binding of troglitazone and other members of the thiazolidinedione family to human liver microsomes, implications for cases of idiosyncratic hepatotoxicity. Proc. N. Am. ISSX Meet., 9th, Nashville, Oct. 24-28, p. 200
74. Smith MT. 2003. Mechanisms of troglitazone hepatotoxicity. Chem. Res. Toxicol. 16:679-87
75. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. 2004. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17:3-16
76. Gupta S, Rogers LK, Taylor SK, Smith CV. 1997. Inhibition of carbamyl phosphate synthetase-I and glutamine synthetase by hepatotoxic doses of acetaminophen in mice. Toxicol. Appl. Pharmacol. 146:317-27
77. Bulera SJ, Birge RB, Cohen SD, Khairallah EA. 1995. Identification of the mouse liver 44-kDa acetaminophen-binding protein as a subunit of glutamine synthetase. Toxicol. Appl. Pharmacol. 134:313-20
78. Ribeiro JM, Costas MJ, Cameselle JC. 1999. ADP-ribosepyrophosphatase-I partially purified from livers of rats overdosed with acetaminophen reveals enzyme inhibition in vivo reverted in vitro by dithiothreitol. J. Biochem. Mol. Toxicol. 13:171-77
79. Ozdemirler G, Aykac G, Uysal M, Oz H. 1994. Liver lipid peroxidation and glutathione-related defence enzyme systems in mice treated with paracetamol. J. Appl. Toxicol. 14:297-99
80. Shirota FN, DeMaster EG, Shoeman DW, Nagasawa HT. 2002. Acetaminophen-induced suppression of hepatic AdoMet synthetase activity is attenuated by prodrugs of L-cysteine. Toxicol. Lett. 132:1-8
81. Senter PD, Al-Abed Y, Metz CN, Benigni F, Mitchell RA, et al. 2002. Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc. Natl. Acad. Sci. USA 99:144-49
82. Pumford NR, Halmes NC, Martin BM, Cook RJ, Wagner C, Hinson JA. 1997. Covalent binding of acetaminophen to N-10-formyltetrahydrofolate dehydrogenase in mice. J. Pharmacol. Exp. Ther. 280:501-5
83. Bruno MK, Khairallah EA, Cohen SD. 1998. Inhibition of protein phosphatase activity and changes in protein phosphorylation following acetaminophen exposure in cultured mouse hepatocytes. Toxicol. Appl. Pharmacol. 153:119-32
84. Pierce RH, Franklin CC, Campbell JS, Tonge RP, Chen W, et al. 2002. Cell culture model for acetaminophen-induced hepatocyte death in vivo. Biochem. Pharmacol. 64:413-24
85. Daya S, Anoopkumar-Dukie S. 2000. Acetaminophen inhibits liver trytophan-2,3-dioxygenase activity with a concomitant rise in brain serotonin levels and a reduction in urinary 5-hydroxyindole acetic acid. Life Sci. 67:235-10
86. Landin JS, Cohen SD, Khairallah EA. 1996. Identification of a 54-kDa mitochondrial acetaminophen-binding protein as aldehyde dehydrogenase. Toxicol. Appl. Pharmacol. 141:299-307
87. Halmes NC, Hinson JA, Martin BM, Pumford NR. 1996. Glutamate dehydrogenase covalently binds to a reactive metabolite of acetaminophen. Chem. Res. Toxicol. 9:541-46
88. Parmar DV, Ahmed G, Khandkar MA, Katyare SS. 1995. Mitochondrial ATPase: a target for paracetamol-induced hepatotoxicity. Eur. J. Pharmacol. 293:225-29
89. 2+ ATPase by acetaminophen. Biochem. Pharmacol. 37:2125-31
90. +-ATPase ion pump during acetaminophen-induced hepatotoxicity in rat. Biochem. Biophys. Res. Commun. 149:203-7
91. Qiu Y, Benet LZ, Burlingame AL. 1998. Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. J. Biol. Chem. 273:17940-53
92. Fountoulakis M, Berndt P, Boelsterli UA, Crameri F, Winter M, et al. 2000. Two-dimensional database of mouse liver proteins: changes in hepatic protein levels following treatment with acetaminophen or its nontoxic regioisomer 3-acetamidophenol. Electrophoresis 21:2148-61
93. Gruchalla RS, Sullivan TJ. 1991. Detection of human IgE to sulfamethoxazole by skin testing with sulfamethoxazoyl-poly-L-tyrosine. J. Allergy Clin. Immunol. 88:784-92
94. Farrell J, Naisbitt DJ, Drummond NS, Depta JP, Vilar FJ, et al. 2003. Characterization of sulfamethoxazole and sulfamethoxazole metabolite-specific T-cell responses in animals and humans. J. Pharmacol. Exp. Ther. 306:229-37
95. Madden S, Maggs JL, Park BK. 1996. Bioactivation of carbamazepine in the rat in vivo. Evidence for the formation of reactive arene oxide(s). Drug Metab. Dispos. 24:469-79
96. Boelsterli UA. 2003. Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol. Appl. Pharmacol. 192:307-22
97. Scheen AJ. 2001. Hepatotoxicity with thiazolidinediones: is it a class effect? Drug Saf. 24:873-88
98. Graham DJ, Green L, Senior JR, Nourjah P. 2003. Troglitazone-induced liver failure: a case study. Am. J. Med. 114:299-306