title: Role of Metabolic Activation in 8-Epidiosbulbin E Acetate-Induced Liver Injury: Mechanism of Action of the Hepatotoxic Furanoid.
abstract: 8-Epidiosbulbin E acetate (EEA), a furanoid, was unexpectedly found to be the most abundant diterpenoid lactone in certain varieties of Dioscorea bulbifera L. (DB), a traditional herbal medicine widely used in Asian nations. This herb has been reported to cause liver injury in humans and experimental animals. The occurrence of EEA in DB was dependent on its commercial source. The present study shows that EEA exhibits time- and dose-dependent liver injury in mice. Pretreatment with ketoconazole prevented the animals from developing EEA-induced liver injury, caused 7- and 13-fold increases in the plasma Cmax and AUC of EEA, and decreased urinary excretion of glutathione conjugates derived from EEA. Pretreatment with buthionine sulfoximine exacerbated EEA-induced hepatotoxicity. In order to define the role of EEA's furan moiety in EEA-induced hepatotoxicity, we synthesized tetrahydro-EEA by catalytic hydrogenation of the furan moiety. No liver injury was observed in the animals given the same doses of tetrahydro-EEA as those used with EAA. The results indicate that EEA itself does not appear to be hepatotoxic but that the electrophilic intermediate generated by the metabolic activation of the furan ring mediated by cytochromes P450 is responsible for EEA-induced liver injury.
authors.forename: Dongju
authors.initials: D
authors.lastname: Lin
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Jiang
authors.forename: Youjun
authors.initials: Y
authors.lastname: Xu
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Gao
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine , Seattle, Washington 98101, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D013997:Time Factors
chemical_list: C534602:8-epidiosbulbin E acetate; D004224:Diterpenes; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole