DNA damage by reactive oxygen species resulting from metabolic activation of 8-epidiosbulbin E acetate in vitro and in vivo

Zhang, Shiyu; Liu, Ying; Liu, Ting; Pan, Jie; Tan, Rong; Hu, Zixia; Gong, Bowen; Liao, Yufen; Luo, Pei; Zeng, Qibing; Li, Weiwei; Zheng, Jiang

doi:10.1016/j.taap.2022.116007

Cited by 6 publications

(2 citation statements)

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“…Our previous work demonstrated that administration of EEA induced acute liver injury in mice, accompanied by elevated ALT/AST levels and liver tissue lesions . Recently, our team found that treatment of mouse primary hepatocytes with EEA resulted in overproduction of reactive oxygen species and DNA damage . Our early study also demonstrated that metabolic activation of the furan moiety played a major role in EEA-induced hepatotoxicity .…”

Section: Introductionmentioning

confidence: 75%

“…11 Recently, our team found that treatment of mouse primary hepatocytes with EEA resulted in overproduction of reactive oxygen species and DNA damage. 12 Our early study also demonstrated that metabolic activation of the furan moiety played a major role in EEA-induced hepatotoxicity. 13 The furan ring of EEA was oxidized by CYP3A4 to the resulting epoxide/cis-enedial intermediates (Scheme 1) which attack hepatic protein to form protein covalent binding.…”

Section: ■ Introductionmentioning

confidence: 84%

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Asparagine and Glutamine Residues Participate in Protein Covalent Binding by Epoxide Metabolite of 8-Epidiosbulbin E Acetate In Vitro and In Vivo

Zhang

Yang

et al. 2022

Chem. Res. Toxicol.

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Dioscorea Bulbifera L. (DBL), an effective traditional Chinese medicine, has been restricted because of multiple reports that it can cause severe hepatotoxicity. 8-Epidiosbulbin E acetate (EEA), one of the main components of DBL, can induce severe liver injury. It has been reported that EEA can be metabolized by CYP3A to the corresponding cis-enedial intermediate which alkylates the lysine residues of proteins to form pyrroline derivatives. The present study unexpectedly found that the reactive intermediate reacted with the amide groups of asparagine (Asn) and glutamine (Gln) residues of hepatic proteins of mice treated with EEA. The amide-derived protein modification increased with the increase in the dose administered. Like the adduction of the primary amine of lysine residues, the electrophilic metabolite reacted with the amide groups of Asn and Gln residues to offer the corresponding pyrrolines. The structures of the pyrrolines were confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy.

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Section: Introductionmentioning

confidence: 75%