The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
CHARACTERIZATION OF UDP-GLUCURONOSYLTRANSFERASES(UGTS)INVOLVED IN THE METABOLISM OF TROGLITAZONE IN RATS AND HUMANS
Yasushi YOSHIGAEKumiko KONNOWataru TAKASAKIToshihiko IKEDA
Author information
Keywords: Hyperbilirubinemia
JOURNALS FREE ACCESS

2000 Volume 25 Issue 5 Pages 433-441

Details
Abstract

UDP-glucuronosyltransferases(UGTs)involved in troglitazone glucuronidation in rats and humans have been characterized to support the previous toxicity study on troglitazone in Gunn rats and to examine whether the UGT polymorphism or inhibition of bilirubin metabolism is related to the clinically reported rare cases of liver failure. The experiments using Gunn rats revealed that UGT1 enzymes are not involved in troglitazone glucuronidation and that the responsible enzyme in rats was suggested to be UGT2B2, an androsterone UGT, by inhibition sudies. In humans, contribution of UGT1A1 was estimated to be about 30% of the total troglitazone glucuronidation by UGTs, using human liver microsomes and recombinant UGTs. Other UGT1 and UGT2 enzymes seem to be responsible for the rest of the troglitazone glucuronidation in humans. The multiplicity of UGTs involved in troglitazone glucuronidation in humans may allow even patients lacking bilirubin UGT(UGT1A1)activity to produce troglitazone glucuronide. These observations suggest that the polymorphism of UGT is not the reason behind the liver failure induced by the troglitazone treatment, and troglitazone does not inhibit bilirubin glucuronidation in clinical treatment. In addition, the increased bilirubin level in the blood of patients who have troglitazone-induced liver failure is a consequence of liver injury and not due to inhibition of bilirubin glucuronidation by troglitazone.

Information related to the author
© The Japanese Society of Toxicology Headquarters
Previous article Next article
feedback
Top