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<p>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 <i>ε</i>-amino group of lysine residues. The formation of the protein adduction was found to be associated with the hepatotoxicity of RGZ.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月13日

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  • Yanjia Zhao,
  • Yi Yang,
  • Zifang Ding,
  • Yao Sun,
  • Mingyu Zhang,
  • Weiwei Li,
  • Ting Liu,
  • Zixia Hu,
  • Ying Peng,
  • Jiang Zheng

摘要

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.