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Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic

  • Toxicokinetics and Metabolism
  • Published:
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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.

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Abbreviations

DIOB:

Diosbulbin B

GSH:

Glutathione

BSO:

Buthionine sulfoximine

DB:

Dioscorea bulbifera L.

ALT:

Alanine transaminase

AST:

Aspartate transaminase

KTC:

Ketoconazole

mBrB:

Monobromobimane

H&E:

Hematoxylin and eosin

C max :

Maximum serum concentration

AUC:

Area under the serum concentration–time curve

T max :

Time required to reach maximum serum concentration

Vz/F :

Distribution of apparent solvent

CLz/F :

Clearance rate

DP:

Declustering potential

CE:

Collision energy

CXP:

Collision cell exit potential

IDA:

Information-dependent acquisition

EPI:

Enhanced product ion

HPLC:

High-performance liquid chromatography

MRM:

Multiple reaction monitor

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (Nos. 81430086 and 81373471).

Conflict of interest

None.

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Authors and Affiliations

  1. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China

    Weiwei Li, Huiyuan Gao, Youjun Xu & Jiang Zheng

  2. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People’s Republic of China

    Dongju Lin & Ying Peng

  3. Department of Clinical Laboratory, The General Hospital of Shenyang Command, Shenyang, People’s Republic of China

    Dongya Meng

  4. Center for Developmental Therapeutics, Seattle Children’s Research Institute, Seattle, WA, USA

    Charles Vincent Smith & Jiang Zheng

  5. Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, 98102, USA

    Jiang Zheng

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  1. Weiwei Li
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  3. Huiyuan Gao
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Correspondence to Ying Peng or Jiang Zheng.

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Li, W., Lin, D., Gao, H. et al. Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic. Arch Toxicol 90, 863–872 (2016). https://doi.org/10.1007/s00204-015-1495-8

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  • DOI: https://doi.org/10.1007/s00204-015-1495-8

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