Rosiglitazone hepatotoxicity resulting from hepatic protein covalent binding derived from its aldehyde metabolite.

Rosiglitazone (RGZ), a thiazolidinedione insulin sensitizer, is widely used in the treatment of type 2 diabetes mellitus. However, concerns regarding its dose-dependent hepatotoxicity have emerged, and the mechanisms of the toxic action remain elusive. This study aimed to investigate the mechanism by which an aldehyde metabolite generated through metabolic activation of RGZ forms covalent adduction with protein lysine residues and its contribution to hepatotoxicity. Using in vitro liver microsomal incubations coupled with LC-MS/MS, the reactive aldehyde metabolite and its corresponding lysine adduct were identified. It was verified that RGZ was primarily metabolized by CYP3A and CYP2E1 into an electrophilic aldehyde metabolite which subsequently underwent covalent bonding with the ε-amino group of lysine residues. The formation of the protein adduction was found to be associated with the hepatotoxicity of RGZ.