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Troglitazone

  • Tsuyoshi YokoiEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

Troglitazone was the first thiazolidinedione antidiabetic agent approved for clinical use in 1997, but it was withdrawn from the market in 2000 due to serious idiosyncratic hepatotoxicity. Troglitazone contains the structure of a unique chroman ring of vitamin E, and this structure has the potential to undergo metabolic biotransformation to form quinone metabolites, phenoxy radical intermediate, and epoxide species. Although troglitazone has been shown to induce apoptosis in various hepatic and nonhepatic cells, the involvement of reactive metabolites in the troglitazone cytotoxicity is controversial. Numerous toxicological tests, both in vivo and in vitro, have been used to try to predict the toxicity, but no direct mechanism has been demonstrated that can explain the hapatotoxicity that occurred in some individuals. This chapter summarizes the proposed mechanisms of troglitazone hepatotoxicity based in vivo and in vitro studies. Many factors have been proposed to contribute to the mechanism underlying this idiosyncratic toxicity.

Keywords

Troglitazone Hepatotoxicity Active metabolites CYP3A Hypersensitivity 

Notes

Acknowledgment

We thank Mr. Brent Bell for reviewing the manuscript.

References

  1. Akai S, Hosomi H, Minami K, Tsuneyama K, Katoh M, Nakajima M, Yokoi T (2007) Knock down of γ-glutamylcysteine synthetase in rat causes acetaminophen-induced hepatotoxicity. J Biol Chem 282:23996-234003PubMedCrossRefGoogle Scholar
  2. Bae MA, Song BJ (2003) Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells. Mol Pharmacol 63:401-408PubMedCrossRefGoogle Scholar
  3. Bae MA, Rhee H, Song BJ (2003) Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines. Toxicol Lett 139:67-75Google Scholar
  4. Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ (2000) Role of quinone in toxicology. Chem Res Toxicol 13:135-160PubMedCrossRefGoogle Scholar
  5. Bourdi M, Larrey D, Nataf J, Bernuau J, Pessayre D, Iwasaki M, Guengerich FP, Beaune PH (1990) Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis. J Clin Invest 85(6):1967-73Google Scholar
  6. Bourdi M, Chen W, Peter RM, Martin JL, Buters JTM, Nelson SD, Pohl LR (1996) Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 9:1159-1166PubMedCrossRefGoogle Scholar
  7. Bova MP, Tam D, McMahon G, Mattson MN (2005) Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells. Toxicol Lett 155:41-50PubMedCrossRefGoogle Scholar
  8. Brown C, Toh BH, Pedersen JS, Clarke FM, Mackay IR, Gust I (1987) Autoantibody to aldolase in acute and chronic hepatitis. Pathology 19:347-350PubMedCrossRefGoogle Scholar
  9. Ciaraldi TP, Gilmore A, Olefsky JM, Goldberg M, Heidenreich KA (1990) In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism 39:1056-1062PubMedCrossRefGoogle Scholar
  10. Fan YH, Chen H, Natarajan A, Guo Y, Harbinski F, Iyasere J, Christ W, Aktas H, Halperin JA (2004) Structure-activity requirements for the antiproliferative effect of troglitazone derivatives mediated by depletion of intracellular calcium. Bio Med Chem Lett 44:2547-2550CrossRefGoogle Scholar
  11. Freid J, Everitt D, Boscia J (2000) Rosiglitazone and hepatic failure. Ann Inter Med 132:164Google Scholar
  12. Fujiwara T, Okuno A, Yoshioka T, Horikoshi H (1995) Suppression of hepatic gluconeogenesis in long-term troglitazone treated diabetic KK and C57BL/KsJ-db/db mice. Metabolism 44:486-490PubMedCrossRefGoogle Scholar
  13. Funk C, Pantze M, Jehle L, Ponelle C, Scheuermann G, Lazendic M, Gasser R (2001a) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of the 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 167:83-98PubMedCrossRefGoogle Scholar
  14. Funk C, Ponelle C, Scheuermann G, Pantze M (2001b) 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 59:627-635PubMedGoogle Scholar
  15. Gardner OS, Shiau CW, Chen CH, Graves LM (2005) Peroxisome proliferator-activated receptor γ-independent activation of p38 MAPK by troglitazone involves calcium/calmodulin-dependent protein kinase II and protein kinase R: Correlation with endoplasmic reticulum stress. J Biol Chem 280:10109-10118PubMedCrossRefGoogle Scholar
  16. Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 355:33-45PubMedCrossRefGoogle Scholar
  17. Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM (1998) Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 129:36-38PubMedGoogle Scholar
  18. Gonzalo P, Lavergne JP, Reboud JP (2001) Pivotal role of the P1 N-terminal domain in the assembly of the mammalian ribosomal stalk and in the proteosynthetic activity. J Biol Chem 276:19762-19769PubMedCrossRefGoogle Scholar
  19. Green S (1995) PPAR: a mediator of peroxisome proliferators action. Mutat Res 333:101-109PubMedCrossRefGoogle Scholar
  20. Gut J, Christen U, Huwyler J (1993) Mechanism of halothane toxicity: Novel insights. Pharmac Ther 58:133-155CrossRefGoogle Scholar
  21. Hagenbuch B, Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609:1-18PubMedCrossRefGoogle Scholar
  22. Hanefeld M (2001) Pharmacokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl 121:19-25PubMedGoogle Scholar
  23. Haskins JR, Rowse P, Rahbari R, de la Iglesa FA (2001) Thiazolidinedione toxicity to isolated hepatocytes revealed by coherent multiprobe fluorescence microscopy and correlated with multiparameter flow cytometry of peripheral leukocytes. Arch Toxicol 75:425-438PubMedCrossRefGoogle Scholar
  24. He K, Woolf TF, Kindt EK, Fielder AE, Talaat RE (2001) Troglitazone quinone formation catalyzed by human and rat CYP3A: An atypical CYP oxidation reaction. Biochem Pahrmacol 62:191-198CrossRefGoogle Scholar
  25. Hewitt NJ, Lloyd S, Haydan M, Butler R, Sakai Y, Springer R, Fackett A, and Li AP (2002) Correlation between troglitazone cytotoxicity and drug metabolic enzyme activities in cryopreserved human hepatocytes. Chem Biol Interact 142:73-82Google Scholar
  26. Holcik M, Sonenberg N (2005) Translational control in stress and apoptosis. Nature Rev Mol Cell Biol 6:318-327CrossRefGoogle Scholar
  27. Homberg JC, Andre C, Abuaf N (1984) A new anti-liver-kidney microsome antibody (andi-LKM2) in tienilic acid-induced hepatitis. Clin Exp Immunol 55:561-570PubMedGoogle Scholar
  28. Honma W, Shimada M, Sasano H, Ozawa S, Miyata M, Nagata K, Ikeda T, Yamazoe Y (2002) Phenol sulfotransferase, ST1A3, as the main enzyme catalyzing sulfation of troglitazone in human liver. Drug Metab Dispos 30:944-952PubMedCrossRefGoogle Scholar
  29. Inoue I, Katayama S, Takahashi K, Negishi K, Miyazaki T, Sonoda M, Komoda T (1997) Troglitazone has a scavenging effect on reactive oxygen species. Biochem Biophys Res Comm 235:113-116PubMedCrossRefGoogle Scholar
  30. Isley WL, Oki JC (2000) Rosiglitazone and liver failure. Ann Intern Med 133:393PubMedGoogle Scholar
  31. Izumi T, Enomoto S, Hoshiyama K, Sasahara K, Sugiyama Y (1997a) Pharmacokinetic stereoselectivity of troglitazone, an antidiabetic agent, in the KK mouse. Biopharm Drug Dispos 18:305-324PubMedCrossRefGoogle Scholar
  32. Izumi T, Hoshiyama K, Enomoto S, Sasahara K, Sugiyama Y (1997b) Pharmacokinetics of troglitazone, an antidiabetic agent: Prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data. J Pharmacol Exp Ther 280:1392-1400PubMedGoogle Scholar
  33. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK and p38 protein kinases. Science 298:1911-1912PubMedCrossRefGoogle Scholar
  34. Ju C, Uetrecht JP (2002) Mechanism of idiosyncratic drug reaction: relative metabolites formation, protein binding and the regulation of the immune system. Curr Drug Metab 3:367-377PubMedCrossRefGoogle Scholar
  35. Jung JY, Yoo CI, Kim HT, Kwon CH, Park JY, Kim YK (2007) Role of mitogen-activated protein kinase (MAPK) in troglitazone-induced osteoblastic cell death. Toxicology 234:73-82PubMedCrossRefGoogle Scholar
  36. Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, Baille TA (2001) Studies on the mechanism 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 14:62-70PubMedCrossRefGoogle Scholar
  37. Kawai K, Kawasaki-Tokui Y, Odaka T, Tsuruta F, Kazui M, Iwabuchi H, Nakamura T, Kinoshita T, Ikeda T, Yoshioka T, Komai T, Nakamura K (1997) Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. Arzneimittelforschung 47:356-368PubMedGoogle Scholar
  38. Kawai K, Odaka T, Tsurata F, Tokui T, Ikeda T, Nakamura K (1998) Stereoselective metabolism of new oral anti-diabetic agent troglitazone stereoisomers in liver. Xenobio Metab Dispos 13:362-368Google Scholar
  39. Kenna JG, Knight TL, van Pelt FNAM (1993) Immunity to halothane metabolite-modified proteins in halothane hepatitis. Ann N Y Acad Sci 685:646-661PubMedCrossRefGoogle Scholar
  40. Kostrubsky VE, Sinclair JF, Ramachandran V, Venkataramanan WYH, Kindt E, Galchev V, Rose K, Sinz M, Strom SC (2000) The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures. Drug Metab Dispos 28:1192-1197PubMedGoogle Scholar
  41. Kostrubsky VE, Vore M, Kindt E, Burliegh J, Rogers K, Peter G, Altogge D, Sinz MW (2001) The effects of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats. Drug Mtab Dispos 29:1561-1566Google Scholar
  42. Kreb R (2006) Implications of genetic polymorphism in drug transporters for pharmacotherapy. Cancer Lett 234:4-33CrossRefGoogle Scholar
  43. Lebovitz HE, Kreider M, Freed MI (2002) Evaluation of liver function in type 2 diabetic patients during clinical trials. Diabetes Care 25:815-821PubMedCrossRefGoogle Scholar
  44. Lee WM (2003) Drug-induced hepatotoxicity. New Engl J Med 349:474-485PubMedCrossRefGoogle Scholar
  45. Leeder JS, Riley RJ, Cook VA, Spielberg SP (1992) Human anti-cytochrome P450 antibodies in aromatic anticonvulsant-induced hypersensitivity reactions. J Pharmacol Exp Ther 263: 360-367PubMedGoogle Scholar
  46. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson T, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome-activated receptor γ (PPARγ). J Biol Chem 270:12953-12956PubMedCrossRefGoogle Scholar
  47. Lim PL, Liu J, Go ML, Belsterli UA (2008) The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci 101:341-349PubMedCrossRefGoogle Scholar
  48. Liu H, Miller E, van de Water B, Stevens JL (1998) Endoplasmic reticulum stress proteins block oxidant-induced Ca2+ increases and cell death. J Biol Chem 273:12858-12862Google Scholar
  49. Lodish HF, Kong N (1990) Perturbation of cellular calcium blocks exit of secretory proteins from the rough endoplasmic reticulum. J Biol Chem 265:10893-10899PubMedGoogle Scholar
  50. Loi CM, Young M, Randinitis E, Vassos A, Koup JR (1999) Clinical pharmacokinetics of troglitazone. Clin Pharmacokinet 37:91-104PubMedCrossRefGoogle Scholar
  51. Maniratanachote R, Minami K, Katoh M, Nakajima M, Yokoi T (2005a) Chaperone proteins involved in troglitazone-induced toxicity in human hepatoma cell lines. Toxicol Sci 83: 293-302PubMedCrossRefGoogle Scholar
  52. Maniratanachote R, Shibata A, Kaneko S, Yamamori I, Wakasugi T, Sawazaki T, Katoh K, Tokudome S, Nakajima M, Yokoi T (2005b) Detection of autoantibody to aldolase B in sera from patients with troglitazone-induced liver dysfunction. Toxicology 216:15-23PubMedCrossRefGoogle Scholar
  53. Maniratanachote R, Minami K, Katoh M, Nakajima M, Yokoi T (2006) Dephosphorylation of ribosomal protein P0 in response to troglitazone-induced cytotoxicity. Toxicol Lett 166: 189-199PubMedCrossRefGoogle Scholar
  54. Masubuchi Y, Kano S, Horie T (2006) Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thazolidinediones. Toxicology 222:233-239PubMedCrossRefGoogle Scholar
  55. Michalski C, Cui Y, Nies AT, Neuhaus P, Zanger UM, Klein K, Eichalbaum M, Keppler D, Konig J (2002) A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J Biol Chem 277:43058-43063PubMedCrossRefGoogle Scholar
  56. Motomura W, Tanno S, Takahashi N, Nagamine M, Fukuda M, Hohgo Y, Okumura T (2005) Involvement of MEK-ERK signaling pathway in the inhibition of cell growth by troglitazone in human pancreatic cancer cell. Biochem Biophys Res Commun 332:89-94PubMedCrossRefGoogle Scholar
  57. Nagasaki S, Abe T, Kawakami A et al (2002) Pioglitazone-induced hepatic injury in a patient previously receiving troglitazone with success. Diabe Med 19:344-348CrossRefGoogle Scholar
  58. Narayanan PK, Hart T, Elcock F, Zhang C, Hahn L, McFarland D, Schwartz L, Morgan DG, Bugelski P (2003) Troglitazone-induced intracellular oxidative stress in rat hepatoma cells: a flow cytometric assessment. Cytometry 52A:28-35CrossRefGoogle Scholar
  59. Neuschwander-Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ, Brunt EM (1998) Troglitazone-induced hepatic failure leading to liver transplantation. Ann Intern Med 129:38-41PubMedGoogle Scholar
  60. Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, Tamai I (2004) Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos 32:291-294PubMedCrossRefGoogle Scholar
  61. Ong MM, Latchoumycandane C, Boelsterli UA (2007) Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci 97:205-213PubMedCrossRefGoogle Scholar
  62. Ott P, Ranek L, Young MA (1998) Pharmacokinetics of troglitazone, a PPAR-g agonist, in patients with hepatic insufficiency. Eur J Clin Pharmacol 54:567-571PubMedCrossRefGoogle Scholar
  63. Palakurthi SS, Aktas H, Grubissich LM, Mortensen RM, Halperin JA (2001) Anticancer effects of thiazolidinediones are independent of peroxisome proliferators-activated receptor γ and mediated by inhibition of translation initiation. Cancer Res 61:6213-6218PubMedGoogle Scholar
  64. Park BK, Pirmohamed M, Kitteringham NR (1998) Role of drug disposition in drug hypersensitivity: a chemical, molecular and clinical perspective. Chem Res Toxicol 11:969-988PubMedCrossRefGoogle Scholar
  65. PDR (1999) Rezulin®. In: Physician’s desk reference, 52nd edn. Medical Economics Company, Inc., Montvale, NJ, pp 2310-2314Google Scholar
  66. PDR (2005a) Actos®. In: Physician’s desk reference, 59th edn. Thomson PDR, Montvale, NJ, pp 3181-3185Google Scholar
  67. PDR (2005b) Avandia®. In: Physician’s desk reference, 59th edn. Thomson PDR, Montvale, NJ, pp 1438-1443Google Scholar
  68. Penhoet E, Rajkumar T, Rutter WJ (1966) Multiple forms of fructose diphosphate aldolase in mammalian tissues. Proc Natl Acad Sci USA 56:1275-1282PubMedCrossRefGoogle Scholar
  69. Pohl LR, Satoh H, Christ DD, Kenna JG (1988) The immunologic and metabolic basis of drug hypersensitivity. Ann Rev Pharmacol 28:367-387CrossRefGoogle Scholar
  70. Prabhu S, Fackett A, Lloyd S, McClellan HA, Terrell CM, Silber PM, Li AP (2002) Identification of glutathione conjugates of troglitazone in human hepatocytes. Chem Biol Interact 142:83-97PubMedCrossRefGoogle Scholar
  71. Preininger K, Stingl H, Englisch R, Furnsinn C, Graf J, Waldhausl W, Roden M (1999) Acute troglitazone action is isolated persused rat liver. Br J Pharmacol 126:372-378PubMedCrossRefGoogle Scholar
  72. Pumford NR, Martin BM, Thomassen D, Burris JA, Kenna JG, Martin JL, Pohl LR (1993) Serum antibodies from halothane hepatitis patients react with the rat endoplasmic reticulum protein Erp72. Chem Res Toxicol 6:609-615PubMedCrossRefGoogle Scholar
  73. Ramachandran V, Kostrubsky VE, Komoroski BJ, Zhang S, Dorko K, Esplen JE, Strom SC, Venkataramanan R (1999) Troglitazone increases cytochrome P-450 3A protein and activity in primary cultures of human hepatocytes. Drug Metab Dispos 27:1194-1199PubMedGoogle Scholar
  74. Robin MA, Maratrat M, Le Roy M, Le Breton FP, Bonierbale E, Dansette P, Ballet F, Mansuy D, Pessayre D (1996) Antigenic targets in tienilic acid hepatitis: Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera. J Clin Invest 98:1471-1480PubMedCrossRefGoogle Scholar
  75. Rothwell C, McGuire EJ, Altrogge DM, Masuda H, de la Iglesia FA (2002) Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone. J Toxicol Sci 27:35-47PubMedCrossRefGoogle Scholar
  76. Sahi J, Hamilton G, Sinz M, Barros S, Huang SM, Lesko LJ, LeCluyse EL (2000) Effects of troglitazone on chromosome P450 enzymes in primary cultures of human and rat hepatocytes. Xenobiotica 30:273-284PubMedCrossRefGoogle Scholar
  77. Saltiel AR, Olefsky JM (1996) Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45:1661-1669PubMedCrossRefGoogle Scholar
  78. Schultz WA, Eickerlmann P, Sies H (1996) Free radicals in toxicology: redox cycling and NAD(P) H:quinone oxidoreductase. Arch Toxicol Suppl 18:217-222CrossRefGoogle Scholar
  79. Sherr CJ, Roberts JM (1999) CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev 13:1501-1512PubMedCrossRefGoogle Scholar
  80. Shiau CW, Yang CC, Kulp SK, Chen KF, Chen CS, Huang JW, Chen CH (2005) Thiazolidinediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xl/Bcl-2 functions independently of PPARγ. Cancer Res 65:1561-1569PubMedCrossRefGoogle Scholar
  81. Shibuya A, Watanabe M, Fujita Y, Saigenji K, Kuwao S, Takahashi H, Takeuchi H (1998) An autopsy case of troglitazone-induced fulminant hepatitis. Diabetes Care 21:2140-2143PubMedCrossRefGoogle Scholar
  82. Simon T, Bacquemont L, Mary-Krause M, de Waziers I, Beaune P, Funck-Brentano C, Jaillon P (2000) Combined glutachione-S-tranferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther 67:432-437PubMedCrossRefGoogle Scholar
  83. Spiegelman BM (1998) PPAR-γ: Adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507-514PubMedCrossRefGoogle Scholar
  84. Takagi S, Nakajima M, Mohri T, Yokoi T (2008) Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem 283:9674-9680PubMedCrossRefGoogle Scholar
  85. 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 14:965-974PubMedCrossRefGoogle Scholar
  86. Tirmenstein MA, Hu CX, Gales TL, Maleeff BE, Narayanan PK, Kurali E, Hart TK, Thomas HC, Schwartz LW (2002) Effects of troglitazone on HepG2 viability and mitochondrial function. Toxicol Sci 69:131-138PubMedCrossRefGoogle Scholar
  87. Toyoda Y, Tsuchida A, Iwami E, Miwa I (2001) Toxic effect of troglitazone on cultured rat hepatocytes. Life Sci 68:1867-1876PubMedCrossRefGoogle Scholar
  88. Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T (2006) MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res 66:9090-9098PubMedCrossRefGoogle Scholar
  89. Vignati L, Turlizzi E, Monaci S, Grossi P, Kanter R, Monshouwer M (2005) An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics. Toxicology 216:154-167PubMedCrossRefGoogle Scholar
  90. Watanabe T, Ohashi Y, Yasuda M, Takaoka M, Furukawa T, Yamoto T, Sanbuissho A, Manabe S (1999) Was it possible to predict liver dysfunction caused by troglitazone during the nonclinical safety studies? Iyakuhin Kenkyu 30:537-546Google Scholar
  91. Watanabe Y, Nakajima M, Yokoi T (2002) Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos 30:1462-1469PubMedCrossRefGoogle Scholar
  92. Watanabe I, Tomita A, Shimizu M, Sugawara M, Yasumo H, Koishi R, Takahashi T, Miyoshi K, Nakamura K, Izumi T, Matsushita Y, Furukawa H, Haruyama H, Koga T (2003) A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin Pharmacol Ther 73:435-455PubMedCrossRefGoogle Scholar
  93. Watkins PB, Whitcomb RW (1998) Hepatic dysfunction associated with troglitazone. N Engl J Med 338:916-917PubMedCrossRefGoogle Scholar
  94. Yamamoto Y, Nakajima M, Yamazaki H, Yokoi T (2001) Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells. Life Sci 70:471-482PubMedCrossRefGoogle Scholar
  95. Yamamoto Y, Yamazaki H, Ikeda T, Watanabe T, Iwabuchi H, Nakajima M, Yokoi T (2002) Formation of a quinone epoxide metabolite of troglitazone with cytotoxic to HepG2 cells. Drug Metab Dispos 30:155-160PubMedCrossRefGoogle Scholar
  96. Yamazaki H, Shibata A, Suzuki M, Nakajima M, Shimada N, Guengerich FP, Yokoi T (1999) Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab Dispos 27:1260-1266PubMedGoogle Scholar
  97. Yoshigae Y, Konno K, Takasaki W, Ikeda T (2000) Characterization of UDP-glucuronosyltransferases (UGTS) involved in the metabolism of troglitazone in rats and humans. J Toxicol Sci 25:433-441PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Faculty of Pharmaceutical Sciences, Drug Metabolism and ToxicologyKanazawa University, Kakuma-machiKanazawaJapan

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