Kai Wang,Dongju Lin,Xiucai Guo,Wenlin Huang,Jiang Zheng,Ying Peng
Diosbulbin B (DIOB), a hepatotoxic furan-containing compound, is a primary ingredient inDioscorea bulbiferaL., a common herbal medicine. Metabolic activation is required for DIOB-induced liver injury. Protein covalent binding of an electrophilic reactive intermediate of DIOB is considered to be one of the key mechanisms of cytotoxicity. A bromine-based analytical technique was developed to characterize the chemical identity of interaction of protein with reactive intermediate of DIOB. Cysteine (Cys) and lysine (Lys) residues were found to react with the reactive intermediate to form three types of protein modification, including Cys adduction, Schiff’s base, and Cys/Lys crosslink. The crosslink showed time- and dose-dependence in animals given DIOB. Ketoconazole pretreatment decreased the formation of the crosslink derived from DIOB, whereas pretreatment with dexamethasone or buthionine sulfoximine increased such protein modification. These data revealed that the levels of hepatic protein adductions were proportional to the severity of hepatotoxicity of DIOB.Keywords:diosbulbin B;hepatotoxicity;protein covalent binding;metabolic activation;bromine-based analytical technique
Yi Yang,Weiwei Li,Yanjia Zhao,Hanqing Xu,Xu Wang,Guode Zhao,Zixia Hu,Ying Peng,Jiang Zheng
Dioscorea bulbifera L. is a traditional Chinese herb. As its principal active component, diosbulbin B (DSB) exhibits anticancer activity by inducing cell cycle arrest and apoptosis. Cell cycle progression relies on chromatin dynamics, which is regulated by histone post-translational modifications (PTMs). DSB is metabolized by CYP3A, resulting in the formation of a cis-enedial reactive intermediate (DDE) that selectively and covalently modifies lysine residues on histones, forming pyrroline derivatives, or in cooperation with glutathione (GSH), forming pyrrole derivatives. These modifications competitively disrupted canonical histone PTMs, accompanied by chromatin decompaction. The formation of these histone adductions and the alteration of histone PTM landscapes were validated in both mouse primary hepatocytes and Cyp3a4-HepG2 cells. Molecular dynamics simulations revealed that DDE-derived lysine adductions impair histone-DNA interactions. The observed covalent modification of histone lysine residues provides a novel strategy by regulating chromatin architecture and a conceptual framework for developing antitumor agents based on epigenetic mechanisms.
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