8-Epidiosbulbin E acetate
(Synonyms: 8-表黄药子素E乙酸酯) 目录号 : GC352008-Epidiosbulbin E acetate 是 Dioscorea bulbifera L. 中存在的丰富的呋喃型化合物,8-Epidiosbulbin E acetate 对多重耐药菌具有广谱的质粒消除活性。8-Epidiosbulbin E acetate 能诱导小鼠肝损伤。
Cas No.:91095-48-6
Sample solution is provided at 25 µL, 10mM.
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8-Epidiosbulbin E acetate, a furanoid, is abundant in Dioscorea bulbifera L.. 8-Epidiosbulbin E acetate exhibits broad-spectrum plasmid-curing activity against multidrug-resistant (MDR) bacteria. 8-Epidiosbulbin E acetate induces liver injury in mice[1][2].
[1]. Shriram V, et al. A potential plasmid-curing agent, 8-epidiosbulbin E acetate, from Dioscorea bulbifera L. against multidrug-resistant bacteria. Int J Antimicrob Agents. 2008 Nov;32(5):405-10. [2]. Lin D, et al. Role of Metabolic Activation in 8-Epidiosbulbin E Acetate-Induced Liver Injury: Mechanism of Action of the Hepatotoxic Furanoid. Chem Res Toxicol. 2016 Mar 21;29(3):359-66.
Cas No. | 91095-48-6 | SDF | |
别名 | 8-表黄药子素E乙酸酯 | ||
Canonical SMILES | CC(O[C@@H]1[C@@]([C@@](C(O2)=O)([H])C[C@@]2([H])C3)([H])[C@]3([H])[C@](C)(C[C@@H](C4=COC=C4)O5)[C@@](C5=O)([H])C1)=O | ||
分子式 | C21H24O7 | 分子量 | 388.41 |
溶解度 | DMSO : 100 mg/mL (257.46 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.5746 mL | 12.873 mL | 25.746 mL |
5 mM | 0.5149 mL | 2.5746 mL | 5.1492 mL |
10 mM | 0.2575 mL | 1.2873 mL | 2.5746 mL |
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给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
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1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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Metabolomic-transcriptomic landscape of 8-Epidiosbulbin E acetate -a major diterpenoid lactone from Dioscorea bulbifera tuber induces hepatotoxicity
Food Chem Toxicol 2020 Jan;135:110887.PMID:31626840DOI:10.1016/j.fct.2019.110887.
Studies have shown that 8-Epidiosbulbin E acetate (EEA), a major diterpenoid lactone in the tuber of Dioscorea bulbifera, can induce hepatotoxicity in vivo. However, the underlying mechanisms remain unknown. Using the integrated transcriptomic and metabolomics method, in this study we investigated the global effect of EEA exposure on the transcriptomic and metabolomic profiles in mice. The abundance of 7131 genes and 42 metabolites in the liver, as well as 43 metabolites in the serum were altered. It should be noted that EEA mainly damaged hepatic cells through the aberrant regulation of multiple systems primarily including bile acid metabolism, and taurine and hypotaurine metabolism. In addition, an imbalance of bile acid metabolism was found to play a key pat in response to EEA-triggered hepatotoxicity. In summary, these findings contributed to understanding the underlying mechanisms of EEA hepatotoxicity.
Evidence for adduction of biologic amines with reactive metabolite of 8-Epidiosbulbin E acetate in vitro and in vivo
Toxicol Lett 2022 Jul 15;365:1-10.PMID:35680040DOI:10.1016/j.toxlet.2022.05.008.
Dioscorea bulbifera L. (DBL) is one of traditional Chinese medicines and has been used for the treatment of goiter, tumor and carbuncles. However, clinic application of the herbal medicine has been limited, due to reported severe hepatotoxicity. 8-Epidiosbulbin E acetate (EEA), one of the major components of DBL, can cause severe liver damage. The furan ring of EEA is metabolized by CYP3A4 to a cis-enedial reactive intermediate prone to react amino and/or thiol groups of amino acid residues. In this study, we investigated the interaction of the reactive intermediate with biologic amines. EEA-derived biologic amine adducts, including spermidine, spermine, putrescine, ornithine, lysine and glutamine were detected in cultured mouse primary hepatocytes treated with EEA. Only spermidine adduct was observed in bile of mice given EEA. The detection of the adducts was established by labeling with bromobenzyl mercaptan and LC-MS/MS analysis. Exposure of EEA resulted in concentration dependent cytotoxicity in hepatocytes. Pretreatment with spermidine attenuated the susceptibility of cells to the cytotoxicity of EEA, because of the compensation of the depleted spermidine.
DNA damage by reactive oxygen species resulting from metabolic activation of 8-Epidiosbulbin E acetate in vitro and in vivo
Toxicol Appl Pharmacol 2022 May 15;443:116007.PMID:35367474DOI:10.1016/j.taap.2022.116007.
8-Epidiosbulbin E acetate (EEA), a furan-containing diterpenoid lactone, is one of main component of Dioscorea bulbifera L. (DBL). It has been reported that EEA induces severe hepatotoxicity in mice and that its hepatotoxicity is associated with metabolic activation. The present study demonstrated that exposure to EEA (50, 100 or 200 μM) induced DNA damage, including significant DNA fragmentation, increases of tail DNA and olive tail moment, H2AX phosphorylation and PARP-1 activation, in cultured mouse primary hepatocytes. Similar observation was obtained in mice administered EEA at 50, 100 or 200 mg/kg. Pre-treatment with 10 μM ketoconazole (KTC), 200 μM vitamin C (VC), or 200 μM glutathione ethyl ester (GSH-OEt) reversed the over-production of reactive oxygen species (ROS) induced by EEA and attenuated susceptibility of hepatocytes to EEA-induced cytotoxicity and DNA damage in mouse primary hepatocytes. In contrast, pre-treatment with 1.0 mM L-buthionine sulfoximine (BSO) potentiated over-production of ROS, cytotoxicity and DNA damage induced by EEA. In summary, EEA induced DNA damage in cultured primary hepatocytes and the liver of mice. ROS, possibly along with DNA alkylation, participated in the observed DNA damage.
Asparagine and Glutamine Residues Participate in Protein Covalent Binding by Epoxide Metabolite of 8-Epidiosbulbin E acetate In Vitro and In Vivo
Chem Res Toxicol 2022 Oct 17;35(10):1821-1830.PMID:35839447DOI:10.1021/acs.chemrestox.2c00130.
Dioscorea Bulbifera L. (DBL), an effective traditional Chinese medicine, has been restricted because of multiple reports that it can cause severe hepatotoxicity. 8-Epidiosbulbin E acetate (EEA), one of the main components of DBL, can induce severe liver injury. It has been reported that EEA can be metabolized by CYP3A to the corresponding cis-enedial intermediate which alkylates the lysine residues of proteins to form pyrroline derivatives. The present study unexpectedly found that the reactive intermediate reacted with the amide groups of asparagine (Asn) and glutamine (Gln) residues of hepatic proteins of mice treated with EEA. The amide-derived protein modification increased with the increase in the dose administered. Like the adduction of the primary amine of lysine residues, the electrophilic metabolite reacted with the amide groups of Asn and Gln residues to offer the corresponding pyrrolines. The structures of the pyrrolines were confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy.
Immunochemical Detection of Protein Modification Derived from Metabolic Activation of 8-Epidiosbulbin E acetate
Chem Res Toxicol 2020 Jul 20;33(7):1752-1760.PMID:32347100DOI:10.1021/acs.chemrestox.0c00016.
Furanoid 8-Epidiosbulbin E acetate (EEA) is one of the most abundant diterpenoid lactones in herbal medicine Dioscorea bulbifera L. (DB). Our early work proved that EEA could be metabolized to EEA-derived cis-enedial (EDE), a reactive intermediate, which is required for the hepatotoxicity observed in experimental animals exposed to EEA. Also, we found that EDE could modify hepatic protein by reaction with thiol groups and/or primary amines of protein. The present study was inclined to develop polyclonal antibodies to detect protein modified by EDE. An immunogen was prepared by reaction of EDE with keyhole limpet hemocyanin (KLH), and polyclonal antibodies were raised in rabbits immunized with the immunogen. Antisera collected from the immunized rabbits demonstrated high titers evaluated by enzyme-linked immunosorbent assays (ELISAs). Immunoblot analysis showed that the polyclonal antibodies recognized EDE-modified bovine serum albumin (BSA) in a hapten load-dependent manner but did not cross-react with native BSA. Competitive inhibition experiments elicited high selectivity of the antibodies toward EDE-modified BSA. The antibodies allowed us to detect and enrich EDE-modified protein in liver homogenates obtained from EEA-treated mice. The developed immunoprecipitation technique, along with mass spectrometry, enabled us to succeed in identifying multiple hepatic proteins of animals given EEA. We have successfully developed polyclonal antibodies with the ability to recognize EDE-derived protein adducts, which is a unique tool for us to define the mechanisms of toxic action of EEA.