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

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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
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2022-07-15 , DOI: 10.1021/acs.chemrestox.2c00130
Na Zhang ₁ , Yi Yang ₁ , Wei Li ₁ , Shenzhi Zhou ₁ , Weiwei Li ₂ , Ying Peng ₁ , Jiang Zheng _{1,

2}

Affiliation

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.

中文翻译：

天冬酰胺和谷氨酰胺残基在体外和体内参与 8-Epidiosbulbin E 乙酸酯的环氧化物代谢物的蛋白质共价结合

Dioscorea Bulbifera L. (DBL) 是一种有效的中药，由于多篇报道称其可引起严重的肝毒性，因此受到限制。8-Epidiosbulbin E acetate (EEA) 是 DBL 的主要成分之一，可导致严重的肝损伤。有报道说EEA可以被CYP3A代谢成相应的顺式-烯二醛中间体，将蛋白质的赖氨酸残基烷基化以形成吡咯啉衍生物。本研究出乎意料地发现，活性中间体与用 EEA 处理的小鼠肝蛋白的天冬酰胺 (Asn) 和谷氨酰胺 (Gln) 残基的酰胺基团发生反应。酰胺衍生的蛋白质修饰随着给药剂量的增加而增加。与赖氨酸残基的伯胺加成一样，亲电子代谢物与 Asn 和 Gln 残基的酰胺基团反应生成相应的吡咯啉。吡咯啉的结构通过质谱和核磁共振光谱证实。

更新日期：2022-07-15

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