title: Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism.
abstract: There is a possibility that serious liver dysfunction rarely observed in diabetic patients given troglitazone is attributable to idiosyncratic abnormalities in liver drug-metabolism. In addition, the results of blood biochemical examinations in serious cases of liver dysfunction showed a tendency for a high level of total bilirubin (T-Bil) over a long period compared with other indicators of liver dysfunction. Thus, we focused on genetic variation of UDP-glucuronosyltransferases (UGTs) that are involved in the conjugation of troglitazone and bilirubin. In this study, Gunn rats, which are hereditarily deficient in the UGT1 family of UGT isozymes, and Wistar rats, the parent strain of Gunn rats, were treated with troglitazone for 3 months at dose levels of 0, 100 or 400 mg/kg to investigate two possibilities: first, whether the genetic deficiency in UGT1s induces an alteration of the metabolic profile of troglitazone followed by liver dysfunction, and second, whether the dosing of troglitazone to Gunn rats which show hyperbilirubinemia result in liver dysfunction. As a result, the metabolic profile of troglitazone in Gunn rats was much the same as that of Wistar rats, suggesting that genetic deficiencies in UGT1s did not influence the metabolic profile of troglitazone. Moreover, no elevation of blood biochemical parameters, such as asparate aminotransferase (AST) and alanine aminotransferase (ALT), or histopathological liver injuries, such as hepatocellular degeneration and necrosis, were observed in either strain of rats, and hyperbilirubinemia in Gunn rats was not aggravated by the dosing of troglitazone. These results strongly suggest that troglitazone was not metabolized by UGT1s but by other UGT isozyme (s) in rats, and that glucuronidation of troglitazone did not compete with glucuronidation of bilirubin in vivo. Thus, it is suggested that high levels of total bilirubin in patients with liver dysfunction induced by troglitazone are attributable to hypofunction due to hepatocellular injury, not to metabolic competition of bilirubin with troglitazone. Moreover, it is also suggested that the deficiency in the UGT1 family of UGT isozymes itself may not be the cause of liver dysfunction associated with troglitazone treatment.
authors.affiliation: Medicinal Safety Research Laboratories, Sankyo, Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Furukawa
authors.forename: S
authors.initials: S
authors.lastname: Sharyo
authors.forename: Y
authors.initials: Y
authors.lastname: Ohashi
authors.forename: M
authors.initials: M
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Takaoka
authors.forename: S
authors.initials: S
authors.lastname: Manabe
mesh_terms: D000818:Animals; D002839:Chromans / Q000097:blood / Q000633:toxicity*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D011110:Polymorphism, Genetic; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013844:Thiazoles / Q000097:blood / Q000633:toxicity*; D045162:Thiazolidinediones; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D014453:Glucuronosyltransferase; D000077288:Troglitazone