Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic

• DOI: 10.1007/s00204-015-1495-8
• Publication Date: 2015-04-07T05:46:02Z
• Authors: Weiwei Li; Dongju Lin; Huiyuan Gao; Youjun Xu; Dongya Meng; Charles Vincent S...; Ying Peng; Jiang Zheng
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Glutathione; Heterocyclic Compounds, 4 or More Rings; 3. Good health; Activation, Metabolic; Mice; Structure-Activity Relationship; 03 medical and health sciences; Ketoconazole; Liver; Animals; Chemical and Drug Induced Liver Injury; Furans; Buthionine Sulfoximine

Diosbulbin B (DIOB), a furanoid, is a major constituent of herbal medicine Dioscorea bulbifera L. Exposure to DIOB caused liver injury in humans and experimental animals. The mechanisms of DIOB-induced hepatotoxicities remain unknown. The present study demonstrated that DIOB induced hepatotoxicities in a time- and dose-dependent manner in mice. H&E stained histopathologic image showed the occurrence of necrosis in the liver obtained from the mice treated with DIOB at dose of 200 mg/kg. Pretreatment with KTC protected the animals from hepatotoxicities and hepatic GSH depletion induced by DIOB, increased area under the concentration-time curve of blood DIOB, decreased urinary excretion of GSH conjugates derived from DIOB, and increased urinary excretion of parent drug. Pretreatment with BSO exacerbated DIOB-induced hepatotoxicities. In order to define the role of furan moiety in DIOB-induced liver toxicities, we replaced the furan of DIOB with a tetrahydrofuran group by chemical hydrogenation of the furan ring of DIOB. No liver injury was observed in the animals given the same doses of tetrahydro-DIOB. The furan moiety was essential for DIOB-induced hepatotoxicities. The results implicate the cis-enedial reactive metabolite of DIOB was responsible for the observed toxicities. The observed modest depletion of hepatic GSH in DIOB-treated animals suggests the actions of one or more reactive metabolites, and the hepatic injury observed could be due at least in part to reactions of these metabolites with crucial biomolecules. Cytochrome P450 3A enzymes are implicated in DIOB-induced hepatotoxicities by catalyzing the formation of the reactive metabolite of DIOB.