title: Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic.
abstract: 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.
authors: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
authors: Weiwei
authors: W
authors: Li
authors: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People's Republic of China.
authors: Dongju
authors: D
authors: Lin
authors: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
authors: Huiyuan
authors: H
authors: Gao
authors: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
authors: Youjun
authors: Y
authors: Xu
authors: Department of Clinical Laboratory, The General Hospital of Shenyang Command, Shenyang, People's Republic of China.
authors: Dongya
authors: D
authors: Meng
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA.
authors: Charles Vincent
authors: CV
authors: Smith
authors: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People's Republic of China. yingpeng1999@163.com.
authors: Ying
authors: Y
authors: Peng
authors: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, People's Republic of China. jiang.zheng@seattlechildrens.org.|Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA. jiang.zheng@seattlechildrens.org.|Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, 98102, USA. jiang.zheng@seattlechildrens.org.
authors: Jiang
authors: J
authors: Zheng
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D005663:Furans / Q000737:chemistry / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism / Q000652:urine; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; C569454:diosbulbin B; C018674:tetrahydrofuran; D019328:Buthionine Sulfoximine; D005978:Glutathione; D007654:Ketoconazole
keywords: Diosbulbin B; Hepatotoxicity; Metabolic activation