Lysine- and cysteine-based protein adductions derived from toxic metabolites of 8-epidiosbulbin E acetate.
Furanoid 8-epidiosbulbin E acetate (EEA) is a major constituent of herbal medicine Dioscorea bulbifera L. (DB), a traditional herbal medicine widely used in Asian nations. Our early studies demonstrated that administration of EEA caused acute hepatotoxicity in mice and the observed toxicity required P450-mediated metabolic activation. Protein modification by reactive metabolites of EEA has been suggested to be an important mechanism of EEA-induced hepatotoxicity. The objectives of the present study were to investigate the interaction of the electrophilic reactive metabolites derived from EEA with lysine and cysteine residues of proteins and to define the correlation of protein adductions of EEA and the hepatotoxicity induced by EEA. EEA-derived cis-enedial was found to modify both lysine and cysteine residues of proteins. The observed modifications increased with the increase in doses administered in the animals. The formation of protein adductions derived from the reactive metabolites of EEA were potentiated by buthionine sulfoximine, but were attenuated by ketoconazole. This work facilitated better understanding of the mechanisms of toxic action of EEA.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
Dongju
D
Lin
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
Kai
K
Wang
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
Xiucai
X
Guo
School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
Huiyuan
H
Gao
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: yingpeng1999@163.com.
Ying
Y
Peng
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, 550004, PR China. Electronic address: zhengneu@yahoo.com.
Jiang
J
Zheng
D065767:Activation, Metabolic; D000818:Animals; D019328:Buthionine Sulfoximine / Q000737:chemistry; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology; D003545:Cysteine / Q000737:chemistry*; D027742:Dioscorea / Q000737:chemistry; D004224:Diterpenes / Q000633:toxicity*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000737:chemistry; D008239:Lysine / Q000737:chemistry*; D008297:Male; D008518:Medicine, East Asian Traditional; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry* / Q000187:drug effects*
C534602:8-epidiosbulbin E acetate; D004224:Diterpenes; D011506:Proteins; D019328:Buthionine Sulfoximine; D008239:Lysine; D003545:Cysteine; D007654:Ketoconazole
8-Epidiosbulbin E acetate; Hepatotoxicity; Protein adductions; cis-Enedial