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Toxins 2017, 9(8), 249; https://doi.org/10.3390/toxins9080249

Chemical Identity of Interaction of Protein with Reactive Metabolite of Diosbulbin B In Vitro and In Vivo

1
School of Pharmacy, Shenyang Pharmaceutical University, P.O. Box 21, 103 Wenhua Road, Shenyang 110016, Liaoning, China
2
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
3
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou, China
4
Wuya College of Innovation, Shenyang Pharmaceutical University, P.O. Box 21, 103 Wenhua Road, Shenyang 110016, Liaoning, China
5
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Nilgun E. Tumer
Received: 10 July 2017 / Revised: 24 July 2017 / Accepted: 28 July 2017 / Published: 14 August 2017
(This article belongs to the Section Plant Toxins)
View Full-Text   |   Download PDF [1726 KB, uploaded 15 August 2017]   |  

Abstract

Diosbulbin B (DIOB), a hepatotoxic furan-containing compound, is a primary ingredient in Dioscorea bulbifera L., 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. View Full-Text
Keywords: diosbulbin B; hepatotoxicity; protein covalent binding; metabolic activation; bromine-based analytical technique diosbulbin B; hepatotoxicity; protein covalent binding; metabolic activation; bromine-based analytical technique
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Wang, K.; Lin, D.; Guo, X.; Huang, W.; Zheng, J.; Peng, Y. Chemical Identity of Interaction of Protein with Reactive Metabolite of Diosbulbin B In Vitro and In Vivo. Toxins 2017, 9, 249.

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