954
Views
58
CrossRef citations to date
0
Altmetric
Review Article

Animal models of idiosyncratic drug-induced liver injury—Current status

&
Pages 723-739 | Received 28 Oct 2010, Accepted 24 Mar 2011, Published online: 04 Jul 2011

References

  • Alvarez-Sanchez R, Montavon F, Hartung T, Pahler A. (2006). Thiazolidinedione bioactivation: A comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry. Chem Res Toxicol 19:1106–1116.
  • Andrade RJ, Robles M, Ulzurrun E, Lucena MI. (2009). Drug-induced liver injury: Insights from genetic studies. Pharmacogenomics 10:1467–1487.
  • Antoine DJ, Williams DP, Park BK. (2008). Understanding the role of reactive metabolites in drug-induced hepatotoxicity: State of the science. Expert Opin Drug Metab Toxicol 4:1415–1427.
  • Antoine DJ, Mercer AE, Williams DP, Park BK. (2009). Mechanism-based bioanalysis and biomarkers for hepatic chemical stress. Xenobiotica 39:565–577.
  • Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. (2000). TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191.
  • Bacon JA, Cramer CT, Petrella DK, Sun EL, Ulrich RG. (1996). Potentiation of hypoxic injury in cultured rabbit hepatocytes by the quinoxalinone anxiolytic, panadiplon. Toxicology 108:9–16.
  • Bauman JN, Kelly JM, Tripathy S, Zhao SX, Lam WW, Kalgutkar AS, Obach RS. (2009). Can in vitro metabolism-dependent covalent binding data distinguish hepatotoxic from nonhepatotoxic drugs? An analysis using human hepatocytes and liver S-9 fraction. Chem Res Toxicol 22:332–340.
  • Benjamin SB, Goodman ZD, Ishak KG, Zimmerman HJ, Irey NS. (1985). The morphologic spectrum of halothane-induced hepatic injury: Analysis of 77 cases. Hepatology 5:1163–1171.
  • Bird GL, Williams R. (1989). Detection of antibodies to a halothane metabolite hapten in sera from patients with halothane-associated hepatitis. J Hepatol 9:366–373.
  • Boelsterli UA. (2003). Diclofenac-induced liver injury: A paradigm of idiosyncratic drug toxicity. Toxicol Appl Pharmacol. 192:307–322.
  • Boelsterli UA, Lim PL. (2007). Mitochondrial abnormalities—A link to idiosyncratic drug hepatotoxicity? Toxicol Appl Pharmacol 220:92–107.
  • Bottiger LE, Dalen E, Hallen B. (1976). Halothane-induced liver damage: An analysis of the material reported to the Swedish Adverse Drug Reaction Committee, 1966–1973. Acta Anaesthesiol Scand 20:40–46.
  • Bourdi M, Amouzadeh HR, Rushmore TH, Martin JL, Pohl LR. (2001). Halothane-induced liver injury in outbred guinea pigs: Role of trifluoroacetylated protein adducts in animal susceptibility. Chem Res Toxicol 14:362–370.
  • Bourdi M, Chen W, Peter RM, Martin JL, Buters JT, Nelson SD, Pohl LR. (1996). Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 9:1159–1166.
  • Buchweitz JP, Ganey PE, Bursian SJ, Roth RA. (2002). Underlying endotoxemia augments toxic responses to chlorpromazine: Is there a relationship to drug idiosyncrasy? J Pharmacol Exp Ther 300:460–467..
  • Bunker JP. (1968). Final report of the National Halothane Study. Anesthesiology 29:231–232.
  • Canalese J, Wyke RJ, Vergani D, Eddleston AL, Williams R. (1981). Circulating immune complexes in patients with fulminant hepatic failure. Gut 22:845–848.
  • Cheng L, You Q, Yin H, Holt M, Franklin C, Ju C. (2009). Effect of polyI:C cotreatment on halothane-induced liver injury in mice. Hepatology 49:215–226.
  • Chojkier M. (2005). Troglitazone and liver injury: In search of answers. Hepatology 41:237–246.
  • Cosgrove BD, King BM, Hasan MA, Alexopoulos LG, Farazi PA, Hendriks BS, Griffith LG, Sorger PK, Tidor B, Xu JJ, Lauffenburger DA. (2009). Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 237:317–330.
  • Cousins MJ, Plummer JL, Hall PD. (1989). Risk factors for halothane hepatitis. Aust N Z J Surg 59:5–14.
  • Cribb AE, McQuaid T, Renton KW. (2001). Effect of lipopolysaccharide (LPS)-evoked host defense activation on hepatic microsomal formation and reduction of sulfamethoxazole hydroxylamine in the rat. Biochem Pharmacol 62:457–459.
  • Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. (2007). Genetic susceptibility to diclofenac-induced hepatotoxicity: Contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132:272–281.
  • Deng X, Stachlewitz RF, Liguori MJ, Blomme EA, Waring JF, Luyendyk JP, Maddox JF, Ganey PE, Roth RA. (2006). Modest inflammation enhances diclofenac hepatotoxicity in rats: Role of neutrophils and bacterial translocation. J Pharmacol Exp Ther 319:1191–1199.
  • Deng X, Luyendyk JP, Zou W, Lu J, Malle E, Ganey PE, Roth RA. (2007). Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 322:852–861.
  • Deng X, Luyendyk JP, Ganey PE, Roth RA. (2009). Inflammatory stress and idiosyncratic hepatotoxicity: Hints from animal models. Pharmacol Rev 61:262–282.
  • Dieckhaus CM, Thompson CD, Roller SG, Macdonald TL. (2002). Mechanisms of idiosyncratic drug reactions: The case of felbamate. Chem Biol Interact 142:99–117.
  • Dugan CM, MacDonald AE, Roth RA, Ganey PE. (2010). A mouse model of severe halothane hepatitis based on human risk factors. J Pharmacol Exp Ther 333:364–372.
  • Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ. (2001). The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 69:223–231.
  • Frost L, Mahoney J, Field J, Farrell GC. (1996). Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs. Hepatology 23:80–86.
  • Fujimoto K, Kumagai K, Ito K, Arakawa S, Ando Y, Oda S, Yamoto T, Manabe S. (2009). Sensitivity of liver injury in heterozygous Sod2 knockout mice treated with troglitazone or acetaminophen. Toxicol Pathol 37:193–200.
  • Fukano M, Amano S, Sato J, Yamamoto K, Adachi H, Okabe H, Fujiyama Y, Bamba T. (2000). Subacute hepatic failure associated with a new antidiabetic agent, troglitazone: A case report with autopsy examination. Hum Pathol 31:250–253.
  • Funk C, Ponelle C, Scheuermann G, Pantze M. (2001). Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: In vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol 59:627–635.
  • Funk C, Pantze M, Jehle L, Ponelle C, Scheuermann G, Lazendic M, Gasser R. (2001). Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology 167:83–98.
  • Ganey PE, Roth RA. (2001). Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents. Toxicology 169:195–208.
  • Ganey PE, Luyendyk JP, Maddox JF, Roth RA. (2004). Adverse hepatic drug reactions: Inflammatory episodes as consequence and contributor. Chem Biol Interact 150:35–51.
  • Gregus Z. (2008). Mechanisms of toxicity. In: Klaassen CD, ed. Casarett & Doull’s Toxicology, The Basic Science of Poisons. 7th ed. New York: McGraw Hill Medical, 45–106.
  • Grillo MP, Knutson CG, Sanders PE, Waldon DJ, Hua F, Ware JA. (2003). Studies on the chemical reactivity of diclofenac acyl glucuronide with glutathione: Identification of diclofenac-S-acyl-glutathione in rat bile. Drug Metab Dispos 31:1327–1336.
  • Grillo MP, Ma J, Teffera Y, Waldon DJ. (2008). A novel bioactivation pathway for 2-[2-(2,6-dichlorophenyl)aminophenyl]ethanoic acid (diclofenac) initiated by cytochrome P450-mediated oxidative decarboxylation. Drug Metab Dispos 36:1740–1744.
  • Hall DB, Macgregor TR. (2007). Case-control exploration of relationships between early rash or liver toxicity and plasma concentrations of nevirapine and primary metabolites. HIV Clin Trials 8:391–399.
  • Han D, Hanawa N, Saberi B, Kaplowitz N. (2006). Mechanisms of liver injury. III. Role of glutathione redox status in liver injury. Am J Physiol Gastrointest Liver Physiol 291:G1–G7
  • Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, Boorman GA, Russo MW, Sackler RS, Harris SC, Smith PC, Tennant R, Bogue M, Paigen K, Harris C, Contractor T, Wiltshire T, Rusyn I, Threadgill DW. (2009). Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res 19:1507–1515.
  • Helvering LM, Richardson KA, Englehardt JA, Richardson FC. (1995). Fialuridine (FIAU) depletes mitochondrial DNA in the liver and heart of rat, dog and monkey during long-term oral administration [abstract]. Am Assoc Cancer Res 36:358.
  • Hijona E, Hijona L, Arenas JI, Bujanda L. (2010). Inflammatory mediators of hepatic steatosis. Mediators Inflamm 2010:837419.
  • Hofmann AF. (1989). Current concepts of biliary secretion. Dig Dis Sci 34:16S–S20
  • Hsiao CJ, Younis H, Boelsterli UA. (2010). Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction. Chem Biol Interact 188:204–213.
  • Ishak KG, Irey NS. (1972). Hepatic injury associated with the phenothiazines. Clinicopathologic and follow-up study of 36 patients. Arch Pathol 93:283–304.
  • Jewell H, Maggs JL, Harrison AC, O’Neill PM, Ruscoe JE, Park BK. (1995). Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25:199–217.
  • Jin R, Yang G, Li G. (2010). Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells. J Leukoc Biol 87:779–789.
  • Kaplowitz N. (2005). Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 4:489–499.
  • Kashimshetty R, Desai VG, Kale VM, Lee T, Moland CL, Branham WS, New LS, Chan EC, Younis H, Boelsterli UA. (2009). Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. Toxicol Appl Pharmacol 238:150–159.
  • Khouri MR, Saul SH, Dlugosz AA, Soloway RD. (1987). Hepatocanalicular injury associated with vitamin A derivative etretinate. An idiosyncratic hypersensitivity reaction. Dig Dis Sci 32:1207–1211.
  • Kleiner DE, Gaffey MJ, Sallie R, Tsokos M, Nichols L, McKenzie R, Straus SE, Hoofnagle JH. (1997). Histopathologic changes associated with fialuridine hepatotoxicity. Mod Pathol 10:192–199.
  • Knapp AC, Todesco L, Beier K, Terracciano L, Sagesser H, Reichen J, Krahenbuhl S. (2008). Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores. J Pharmacol Exp Ther 324:568–575.
  • Kostrubsky SE, Strom SC, Kalgutkar AS, Kulkarni S, Atherton J, Mireles R, Feng B, Kubik R, Hanson J, Urda E, Mutlib AE. (2006). Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci 90:451–459.
  • Labbe G, Pessayre D, Fromenty B. (2008). Drug-induced liver injury through mitochondrial dysfunction: Mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 22:335–353.
  • Lee YH, Chung MC, Lin Q, Boelsterli UA. (2008). Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2(+/−) mice: Two-stage oxidative injury. Toxicol Appl Pharmacol 231:43–51.
  • Lewis W, Griniuviene B, Tankersley KO, Levine ES, Montione R, Engelman L, de Court Ascenzi MA, Hornbuckle WE, Gerin JL, Tennant BC. (1997). Depletion of mitochondrial DNA, destruction of mitochondria and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax). Lab Invest 76:77–87.
  • Lheureux PE, Hantson P. (2009). Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 47:101–111.
  • Li AP. (2002). A review of the common properties of drugs with idiosyncratic hepatotoxicity and the “multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 142:7–23.
  • Lim PL, Liu J, Go ML, Boelsterli UA. (2008). The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci 101:341–349.
  • Lind RC, Gandolfi AJ, Hall PD. (1992a). Subanesthetic halothane is hepatotoxic in the guinea pig. Anesth Analg 74:559–563.
  • Lind RC, Gandolfi AJ, Hall PM. (1992b). Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs. Anesthesiology 77:721–727.
  • Lind RC, Gandolfi AJ, Hall PM. (1994). A model for fatal halothane hepatitis in the guinea pig. Anesthesiology 81:478–487.
  • Lind RC, Gandolfi AJ. (1997). Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. Toxicol Appl Pharmacol 142:201–207.
  • Lu J, Roth RA, Ganey PE. (2009). Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats. Toxicologist 102(S-1):452.
  • Lucena MI, Andrade RJ, Martinez C, Ulzurrun E, Garcia-Martin E, Borraz Y, Fernandez MC, Romero-Gomez M, Castiella A, Planas R, Costa J, Anzola S, Agundez JA. (2008). Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology 48:588–596.
  • Luyendyk JP, Maddox JF, Cosma GN, Ganey PE, Cockerell GL, Roth RA. (2003). Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. J Pharmacol Exp Ther 307:9–16.
  • Luyendyk JP, Maddox JF, Green CD, Ganey PE, Roth RA. (2004). Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats. Hepatology 40:1342–1351.
  • Luyendyk JP, Shaw PJ, Green CD, Maddox JF, Ganey PE, Roth RA. (2005). Coagulation-mediated hypoxia and neutrophil-dependent hepatic injury in rats given lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 314:1023–1031.
  • Luyendyk JP, Lehman-McKeeman LD, Nelson DM, Bhaskaran VM, Reilly TP, Car B. D, Cantor GH, Deng X, Maddox JF, Ganey PE, Roth RA. (2006). Coagulation-dependent gene expression and liver injury in rats given lipopolysaccharide with ranitidine but not with famotidine. J Pharmacol Exp Ther 317:635–643.
  • Mancy A, Antignac M, Minoletti C, Dijols S, Mouries V, Duong NT, Battioni P, Dansette PM, Mansuy D. (1999). Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: Particular efficiency and regioselectivity of P450 2Cs. Biochemistry 38:14264–14270.
  • Marion TL, Leslie EM, Brouwer KL. (2007). Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity. Mol Pharm 4:911–918.
  • Masubuchi Y (2006). Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: A review. Drug Metab Pharmacokinet 5:347–356.
  • Mathieu A, Dipadua D, Kahan B. D, Galdabini JJ, Mills J. (1975). Correlation between specific immunity to a metabolite of halothane and hepatic lesions after multiple exposures. Anesth Analg 54:332–339.
  • McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, Savarese B, Kleiner D, Tsokos M, Luciano C. (1995). Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med 333:1099–1105.
  • Mehendale HM. (2005). Tissue repair: An important determinant of final outcome of toxicant-induced injury. Toxicol Pathol 33:41–51.
  • Miyamoto G, Zahid N, Uetrecht JP. (1997). Oxidation of diclofenac to reactive intermediates by neutrophils, myeloperoxidase, and hypochlorous acid. Chem Res Toxicol 10:414–419.
  • Morita M, Akai S, Hosomi H, Tsuneyama K, Nakajima M, Yokoi T. (2009). Drug-induced hepatotoxicity test using gamma-glutamylcysteine synthetase knockdown rat. Toxicol Lett 189:159–165.
  • Murphy EJ, Davern TJ, Shakil AO, Shick L, Masharani U, Chow H, Freise C, Lee WM, Bass NM. (2000). Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group. Dig Dis Sci 45:549–553.
  • Mushin WW, Rosen M, Jones EV. (1971). Post-halothane jaundice in relation to previous administration of halothane. BMJ 3:18–22.
  • Nakayama S, Atsumi R, Takakusa H, Kobayashi Y, Kurihara A, Nagai Y, Nakai D, Okazaki O. (2009). A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding. Drug Metab Dispos 37:1970–1977.
  • Nassar AE, Lopez-Anaya A. (2004). Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov Dev 7:126–136.
  • Neuberger JM, Kenna JG, Williams R. (1987). Halothane hepatitis: Attempt to develop an animal model. Int J Immunopharmacol 9:123–131.
  • Ong MM, Wang AS, Leow KY, Khoo YM, Boelsterli UA. (2006). Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/−) mice. Free Radic Biol Med 40:420–429.
  • Ong MM, Latchoumycandane C, Boelsterli UA. (2007). Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci 97:205–213.
  • Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. (2005). The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol 45:177–202.
  • Pessayre D, Fromenty B, Mansouri A, Berson A. (2003). Hepatotoxicity due to mitochondrial injury. In: Kaplowitz N, DeLeve LD, eds. Drug-Induced Liver Disease. New York: Marcel Dekker, 55–83.
  • Petersen KU. (2002). From toxic precursors to safe drugs. Mechanisms and relevance of idiosyncratic drug reactions. Arzneimittelforschung 52:423–429.
  • Plummer JL, Hall PD, Jenner MA, Cousins MJ. (1987). Hepatic effects of repeated halothane anesthetics in the hypoxic rat model. Anesthesiology 67:355–360.
  • Popovic M, Caswell JL, Mannargudi B, Shenton JM, Uetrecht JP. (2006). Study of the sequence of events involved in nevirapine-induced skin rash in Brown Norway rats. Chem Res Toxicol 19:1205–1214.
  • Rana SV, Pal R, Vaiphie K, Singh K. (2006). Effect of different oral doses of isoniazid-rifampicin in rats. Mol Cell Biochem 289:39–47.
  • Richardson FC, Engelhardt JA, Bowsher RR. (1994). Fialuridine accumulates in DNA of dogs, monkeys, and rats following long-term oral administration. Proc Natl Acad Sci U S A 91:12003–12007.
  • Richardson FC, Tennant BC, Meyer DJ, Richardson KA, Mann PC, McGinty GR, Wolf JL, Zack PM, Bendele RA. (1999). An evaluation of the toxicities of 2′-fluorouridine and 2′-fluorocytidine-HCl in F344 rats and woodchucks (Marmota monax). Toxicol Pathol 27:607–617.
  • Roth RA, Harkema JR, Pestka JP, Ganey PE. (1997). Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents? Toxicol Appl Pharmacol 147:300–311.
  • Roth RA, Ganey PE. (2010). Intrinsic versus idiosyncratic drug-induced hepatotoxicity—Two villains or one? J Pharmacol Exp Ther 332:692–697.
  • Sallie R, Kleiner D, Richardson F, Conjeevaram H, Zullo S, Mutimer D, Hoover S. (1994). Mechanisms of FIAU induced hepatotoxicity [abstract]. Hepatology 20:209A.
  • Sallustio BC, Sabordo L, Evans AM, Nation RL. (2000). Hepatic disposition of electrophilic acyl glucuronide conjugates. Curr Drug Metab 1:163–80.
  • Santos NA, Medina WS, Martins NM, Mingatto FE, Curti C, Santos AC. (2008). Aromatic antiepileptic drugs and mitochondrial toxicity: Effects on mitochondria isolated from rat liver. Toxicol In Vitro 22:1143–1152.
  • Seitz S, Kretz-Rommel A, Oude Elferink RP, Boelsterli UA. (1998). Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2). Chem Res Toxicol 11:513–519.
  • Senior JR. (2008). What is idiosyncratic hepatotoxicity? What is it not? Hepatology 47:1813–1815.
  • Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA. (2007). Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 100:259–266.
  • Shaw PJ, Beggs KM, Sparkenbaugh EM, Dugan CM, Ganey PE, Roth RA. (2009a). Trovafloxacin enhances TNF-induced inflammatory stress and cell death signaling and reduces TNF clearance in a murine model of idiosyncratic hepatotoxicity. Toxicol Sci 111:288–301.
  • Shaw PJ, Ditewig AC, Waring JF, Liguori MJ, Blomme EA, Ganey PE, Roth RA. (2009b). Coexposure of mice to trovafloxacin and lipopolysaccharide, a model of idiosyncratic hepatotoxicity, results in a unique gene expression profile and interferon gamma-dependent liver injury. Toxicol Sci 107:270–280.
  • Shaw PJ, Fullerton AM, Scott MA, Ganey PE, Roth RA. (2009c). The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability. Toxicol Appl Pharmacol 236:293–300.
  • Shaw PJ, Ganey PE, Roth RA. (2009d). Tumor necrosis factor alpha is a proximal mediator of synergistic hepatotoxicity from trovafloxacin/lipopolysaccharide coexposure. J Pharmacol Exp Ther 328:62–68.
  • Shaw PJ, Ganey PE, Roth RA. (2009e). Trovafloxacin enhances the inflammatory response to a Gram-negative or a Gram-positive bacterial stimulus resulting in neutrophil-dependent liver injury in mice. J Pharmacol Exp Ther 330:72–78.
  • Shaw PJ, Ganey PE, Roth RA. (2010). Idiosyncratic, drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 118:7–18.
  • Shenton JM, Chen J, Uetrecht JP. (2004). Animal models of idiosyncratic drug reactions. Chem Biol Interact 150:53–70.
  • Shin NY, Liu Q, Stamer SL, Liebler DC. (2007). Protein targets of reactive electrophiles in human liver microsomes. Chem Res Toxicol 20:859–867.
  • Stevenson W, Gaffey M, Ishitani M, McCullough C, Dickson R, Caldwell S, Lobo P, Pruett T. (1995). Clinical course of four patients receiving the experimental antiviral agent fialuridine for the treatment of chronic hepatitis B infection. Transplant Proc 27:1219–1221.
  • Takakusa H, Masumoto H, Yukinaga H, Makino C, Nakayama S, Okazaki O, Sudo K. (2008). Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab Dispos 36:1770–1779.
  • Takeuchi O, Akira S. (2010). Pattern recognition receptors and inflammation. Cell 140:805–820.
  • Tang W. (2003). The metabolism of diclofenac—Enzymology and toxicology perspectives. Curr Drug Metab 4:319–329.
  • Tang W. (2007). Drug metabolite profiling and elucidation of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 3:407–420.
  • Tasduq SA, Kaiser P, Sharma SC, Johri RK. (2007). Potentiation of isoniazid-induced liver toxicity by rifampicin in a combinational therapy of antitubercular drugs (rifampicin, isoniazid and pyrazinamide) in Wistar rats: A toxicity profile study. Hepatol Res 37:845–853.
  • Tay VK, Wang AS, Leow KY, Ong MM, Wong KP, Boelsterli UA. (2005). Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro. Free Radic Biol Med 39:949–959.
  • Tennant BC, Baldwin BH, Graham LA, Ascenzi MA, Hornbuckle WE, Rowland PH, Tochkov IA, Yeager AE, Erb HN, Colacino JM, Lopez C, Engelhardt JA, Bowsher RR, Richardson FC, Lewis W, Cote PJ, Korba BE, Gerin JL. (1998). Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection. Hepatology 28:179–191.
  • Tukov FF, Maddox JF, Amacher DE, Bobrowski WF, Roth RA, Ganey PE. (2006). Modeling inflammation-drug interactions in vitro: A rat Kupffer cell-hepatocyte coculture system. Toxicol In Vitro 20:1488–1499.
  • Tukov FF, Luyendyk JP, Ganey PE, Roth RA. (2007). The role of tumor necrosis factor alpha in lipopolysaccharide/ranitidine-induced inflammatory liver injury. Toxicol Sci 100:267–280.
  • Uetrecht J. (1991). Metabolism of drugs by activated leukocytes: Implications for drug-induced lupus and other drug hypersensitivity reactions. Adv Exp Med Biol 283:121–132.
  • Uetrecht J. (2007). Idiosyncratic drug reactions: Current understanding. Annu Rev Pharmacol Toxicol 47:513–539.
  • Uetrecht J. (2008). Idiosyncratic drug reactions: Past, present, and future. Chem Res Toxicol 21:84–92.
  • Ulrich RG. (2007). Idiosyncratic toxicity: A convergence of risk factors. Annu Rev Med 58:17–34.
  • Ulrich RG, Bacon JA, Branstetter DG, Cramer CT, Funk GM, Hunt CE, Petrella DK, Sun EL. (1995). Induction of a hepatic toxic syndrome in the Dutch-belted rabbit by a quinoxalinone anxiolytic. Toxicology 98:187–198.
  • Ulrich RG, Bacon JA, Cramer CT, Petrella DK, Sun EL, Meglasson MD, Holmuhamedov E. (1998). Disruption of mitochondrial activities in rabbit and human hepatocytes by a quinoxalinone anxiolytic and its carboxylic acid metabolite. Toxicology 131:33–47.
  • Ulrich RG, Bacon JA, Brass EP, Cramer CT, Petrella DK, Sun EL. (2001). Metabolic, idiosyncratic toxicity of drugs: Overview of the hepatic toxicity induced by the anxiolytic, panadiplon. Chem Biol Interact 134:251–270.
  • Wang EJ, Casciano CN, Clement RP, Johnson WW. (2003). Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: Evidence for contingent unequal binding sites. Pharm Res 20:537–544.
  • Waring JF, Anderson MG. (2005). Idiosyncratic toxicity: Mechanistic insights gained from analysis of prior compounds. Curr Opin Drug Discov Dev 8:59–65.
  • Waring JF, Liguori MJ, Luyendyk JP, Maddox JF, Ganey PE, Stachlewitz RF, North C, Blomme EA, Roth RA. (2006). Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 316:1080–1087.
  • Watkins PB. (1990). Role of cytochromes P450 in drug metabolism and hepatotoxicity. Semin Liver Dis 10:235–250.
  • Watkins PB. (2005). Idiosyncratic liver injury: Challenges and approaches. Toxicol Pathol 33:1–5.
  • Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC. (2006). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized controlled trial. JAMA 296:87–93.
  • Wen B, Coe KJ, Rademacher P, Fitch WL, Monshouwer M, Nelson SD. (2008). Comparison of in vitro bioactivation of flutamide and its cyano analogue: Evidence for reductive activation by human NADPH:Cytochrome P450 reductase. Chem Res Toxicol 21:2393–406.
  • Wen B, Chen Y, Fitch WL. (2009). Metabolic activation of nevirapine in human liver microsomes: Dehydrogenation and inactivation of cytochrome P450 3A4. Drug Metab Dispos 37:1557–1562.
  • Xu JJ, Henstock PV, Dunn MC, Smith AR, Chabot JR, de Graaf D. (2008). Cellular imaging predictions of clinical drug-induced liver injury. Toxicol Sci 105:97–105.
  • You Q, Cheng, L, Reilly T. P. Wegmann, D, Ju C. (2006). Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 44:1421–1431.
  • Zhou S. (2003). Separation and detection methods for covalent drug-protein adducts. J Chromatogr B Analyt Technol Biomed Life Sci 797:63–90.
  • Zou W, Beggs KM, Sparkenbaugh EM, Jones AD, Younis HS, Roth RA, Ganey PE. (2009a). Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury. J Pharmacol Exp Ther 331:114–121.
  • Zou W, Devi SS, Sparkenbaugh E, Younis HS, Roth RA, Ganey PE. (2009b). Hepatotoxic interaction of sulindac with lipopolysaccharide: Role of the hemostatic system. Toxicol Sci 108:184–193.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.