{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T08:49:21Z","timestamp":1768034961273,"version":"3.49.0"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2003,5,17]],"date-time":"2003-05-17T00:00:00Z","timestamp":1053129600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2003,5]]},"abstract":"<jats:sec><jats:title>Background and objective<\/jats:title><jats:p>Troglitazone is a 2,4\u2010thiazolidinedione antidiabetic agent with insulin\u2010sensitizing activities. This agent had been used efficiently in a large number of patients but was withdrawn from the market in March 2000 because of its association with idiosyncratic hepatotoxicity. To address the susceptible genetic factors responsible for the hepatotoxicity associated with this agent, we performed a genetic polymorphic analysis by a target gene approach in troglitazone\u2010treated Japanese patients with type 2 diabetes mellitus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>One hundred ten patients treated with troglitazone were recruited into this study. The case patients (n = 25) were recruited through medical professionals who had previously reported abnormal increases in the levels of ALT or AST among their patients. The control patients (n = 85) were recruited through physicians prescribing troglitazone. For statistical accuracy, efforts were made to maximize the size of the case group. Genotype analysis was performed in 68 polymorphic sites of 51 candidate genes related to drug metabolism, apoptosis, roduction and elimination of reactive oxygen species, and signal transduction pathways of peroxisome proliferator\u2013activated receptor gamma 2 and insulin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The strong correlation with transaminase elevations was observed in the combined glutathione\u2010S\u2010transferase <jats:italic>GSTT1<\/jats:italic>\u2010<jats:italic>GSTM1<\/jats:italic> null genotype (odds ratio, 3.692; 95% confidence interval, 1.354\u201010.066; <jats:italic>P<\/jats:italic> = .008).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The double null mutation of <jats:italic>GSTT1<\/jats:italic> and <jats:italic>GSTM1<\/jats:italic> might influence troglitazone\u2010associated abnormal increases of liver enzyme levels.<\/jats:p><jats:p><jats:italic>Clinical Pharmacology &amp; Therapeutics<\/jats:italic> (2003) <jats:bold>73<\/jats:bold>, 435\u2013455; doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1016\/S0009-9236(03)00014-6\">10.1016\/S0009\u20109236(03)00014\u20106<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1016\/s0009-9236(03)00014-6","type":"journal-article","created":{"date-parts":[[2003,5,12]],"date-time":"2003-05-12T23:54:49Z","timestamp":1052783689000},"page":"435-455","source":"Crossref","is-referenced-by-count":157,"title":["A study to survey susceptible genetic factors responsible for troglitazone\u2010associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus"],"prefix":"10.1111","volume":"73","author":[{"given":"Ichiro","family":"Watanabe","sequence":"first","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiko","family":"Tomita","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miho","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mie","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Yasumo","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuta","family":"Koishi","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tohru","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouichi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Izumi","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuyuki","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidehiko","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Haruyama","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratories Pharmacokinetics and Drug Delivery Research Laboratories, and Regulatory Affairs Department, Sankyo Co, Ltd.  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