A metabolism-based approach to elucidating the mechanism of liver dysfunction induced by troglitazone

We investigated whether or not the liver dysfunction in patientst reated with troglitazone (TG) is related to polymorphism in UDP-glucuronosyltransferases (UGTs), which are partially responsiblef or TG metabolism. In the toxicologicasl tudy of TG using Gunn rats, which are hereditarily deficient in the UGT1 family, the metabolic profile of TG in Gunn rats was very similar to that of Wistar rats, the parent strain of Gunn rats, and no sign of the liver dysfunction was observed in both rats. UGTs involved in TG glucuronidation in rats and humans have been characterized. The experiments using liver microsomes of Gunn rats suggestedt hat the enzymer esponsible for glucuronidation in rats was UGT2B2, an androsterone UGT, by inhibition studies. In humans, contribution of UGT1A1 was estimatedto be about 30% of the total TG glucuronidation by UGTs, using human liver microsomes and recombinant UGTs. Other UGT1 and UGT2 enzymes seem to be responsible for the remaining 70% of TG glucuronidation. The multiplicity of UGTs involved in TG glucuronidation in humans may even allow patients lacking bilirubin UGT (UGT1A1) activity to metabolize TG to the glucuronide. These observation suggest that the polymorphism of UGT is not the reason for the liver dysfunction induced by the TG treatment.