The thiazolidinediones (TZD), such as troglitazone, rosiglitazone, and pioglitazone, are insulin-sensitizing drugs that have been used for treatment of type 2 diabetes. The therapeutic effect of the TZDs is attributed to their activation of the peroxisome proliferators-activated receptor-γ transcription factor that regulates the expression of genes involved in glucose and lipid metabolism. It is well known that the TZDs also exhibit cardiovascular and antihypertensive effects via alternate, poorly defined mechanisms. These agents also exhibit hepatotoxicity, and troglitazone is known to be particularly prone to the effects of toxicity. The nuclear receptor farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis that also has roles in the regulation of cholesterol, lipid, and glucose metabolism. In this issue, Kaimal et al., describes a study that tested whether the TZDs might affect FXR signaling. It was found that troglitazone, but not rosiglitazone or pioglitazone, modulated the expression of FXR target genes. Troglitazone specifically was found to be a partial agonist of FXR. Molecular modeling of troglitazone and the crystal structure of the FXR ligand-binding domain gave a good fit that was dominated by the binding of the troglitazone α-tocopherol side chain within a deep pocket in FXR. These results demonstrate that troglitazone potently antagonizes bile acid-induced expression of FXR target genes and that this activity might represent a mechanism for troglitazone activity and toxicity.
See article at J Pharmacol Exp Ther 2009, 330:125–134.
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