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题名: Characterization of Phase I Metabolism of Resibufogenin and Evaluation of the Metabolic Effects on Its Antitumor Activity and Toxicity
作者: Ning, Jing1, 3;  Yu, Zhen-Long1;  Hu, Liang-Hai2;  Wang, Chao1, 4, 5;  Huo, Xiao-Kui1;  Deng, Sa1;  Hou, Jie1;  Wu, Jing-Jing3;  Ge, Guang-Bo3;  Ma, Xiao-Chi1;  Yang, Ling3
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2015-03-01
DOI: 10.1124/dmd.114.060996
卷: 43, 期:3, 页:299-308
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has displayed great potential as a chemotherapeutic agent in oncology. However, it is a digoxinlike compound that also exhibits extremely cardiotoxic effects. The present study aimed to characterize the metabolic behaviors of RB in humans as well as to evaluate the metabolic effects on its bioactivity and toxicity. The phase I metabolic profile in human liver microsomes was characterized systemically, and the major metabolite was identified as marinobufagenin (5 beta-hydroxylresibufogenin, 5-HRB) by liquid chromatography-mass spectrometry and nuclear magnetic imaging techniques. Both cytochrome P450 (P450) reaction phenotyping and inhibition assays using P450-selective chemical inhibitors demonstrated that CYP3A4 was mainly involved in RB 5 beta-hydroxylation with much higher selectivity than CYP3A5. Kinetic characterization demonstrated that RB 5 beta-hydroxylation in both human liver microsomes and human recombinant CYP3A4 obeyed biphasic kinetics and displayed similar apparent kinetic parameters. Furthermore, 5-HRB could significantly induce cell growth inhibition and apoptosis in A549 and H1299 by facilitating apoptosome assembly and caspase activation. Meanwhile, 5-HRB displayed very weak cytotoxicity of human embryonic lung fibroblasts, and in mice there was a greater tolerance to acute toxicity. In summary, CYP3A4 dominantly mediated 5b-hydroxylation and was found to be a major metabolic pathway of RB in the human liver, whereas its major metabolite (5-HRB) displayed better druglikeness than its parent compound RB. Our findings lay a solid foundation for RB metabolism studies in humans and encourage further research on the bioactive metabolite of RB.
关键词[WOS]: CARDIAC-GLYCOSIDES ;  BUFADIENOLIDES ;  PREECLAMPSIA ;  MARINOBUFAGENIN ;  INHIBITION ;  PREVENTS ;  CHANSU ;  MODEL ;  VITRO ;  RATS
语种: 英语
WOS记录号: WOS:000352002200001
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/146151
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Dalian Med Univ, Coll Pharm, Res Inst Integrated Tradit & Western Med, Dalian 116044, Peoples R China
2.Jilin Univ, Minist Educ, Key Lab Mol Enzymol & Engn, Changchun 130023, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
4.Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China
5.Peking Union Med Coll, Beijing 100021, Peoples R China

Recommended Citation:
Ning, Jing,Yu, Zhen-Long,Hu, Liang-Hai,et al. Characterization of Phase I Metabolism of Resibufogenin and Evaluation of the Metabolic Effects on Its Antitumor Activity and Toxicity[J]. DRUG METABOLISM AND DISPOSITION,2015,43(3):299-308.
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