DICP OpenIR
Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu
Dai, Zi-Ru1,2; Ning, Jing3; Sun, Gui-Bo1,2; Wang, Ping4; Zhang, Feng4; Ma, Hong-Ping4; Zou, Li-Wei4; Hou, Jie3; Wu, Jing-Jing5; Ge, Guang-Bo4,5; Sun, Xiao-Bo1,2; Yang, Ling4
Corresponding AuthorGe, Guang-Bo(geguangbo@dicp.ac.cn) ; Sun, Xiao-Bo(sun_xiaobo@163.com)
Keywordbufotalin cytochrome P450 3A (CYP3A) hydroxylation human liver microsomes (HLMs) docking simulations
Source PublicationFRONTIERS IN PHARMACOLOGY
2019-02-04
ISSN1663-9812
DOI10.3389/fphar.2019.00052
Volume10Pages:10
Funding ProjectNational Key Research and Development Program of China[2017YFC1700200] ; National Key Research and Development Program of China[2017YFC1702000] ; NSF of China[81573501] ; NSF of China[81773810] ; NSF of China[81773687] ; NSF of China[81503152] ; NSF of China[81803627] ; Program of Shanghai Academic/Technology Research Leader[18XD1403600] ; Shuguang Program - Shanghai Education Development Foundation[18SG40] ; Shuguang Program - Shanghai Municipal Education Commission[18SG40] ; Beijing Natural Science Foundation[7184229] ; CAMS Innovation Fund for Medical Sciences (CIFMS)[2017-I2M-1-013] ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities[2017350015] ; China Postdoctoral Science Foundation[2017M610063] ; China Postdoctoral Science Foundation[2018T110072]
Funding OrganizationNational Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation
WOS SubjectPharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy
WOS KeywordPHASE-I METABOLISM ; ISOFORM-SPECIFIC PROBE ; HUMAN LIVER-MICROSOMES ; DRUG-DRUG INTERACTION ; CYTOTOXIC BUFADIENOLIDES ; ACTIVE-SITE ; VITRO ; BINDING ; BUFALIN ; HYDROXYLATION
AbstractBufotalin (BFT), one of the naturally occurring bufodienolides, has multiple pharmacological and toxicological effects including antitumor activity and cardiotoxicity. This study aimed to character the metabolic pathway(s) of BFT and to identify the key drug metabolizing enzyme(s) responsible for hepatic metabolism of BFT in human, as well as to explore the related molecular mechanism of enzymatic selectivity. The major metabolite of BFT in human liver microsomes (HLMs) was fully identified as 5 beta-hydroxylbufotalin by LC-MS/MS and NMR techniques. Reaction phenotyping and chemical inhibition assays showed that CYP3A4 and CYP3A5 were key enzymes responsible for BFT 5 beta-hydroxylation. Kinetic analyses demonstrated that BFT 5 beta-hydroxylation in both HLMs and human CYP3A4 followed the biphasic kinetics, while BFT 5 beta-hydroxylation in CYP3A5 followed substrate inhibition kinetics. Furthermore, molecular docking simulations showed that BFT could bind on two different ligand-binding sites on both CYP3A4 and CYP3A5, which partially explained the different kinetic behaviors of BFT in CYP3A4 and CYP3A5. These findings are very helpful for elucidating the phase I metabolism of BFT in human and for deeper understanding the key interactions between CYP3A enzymes and bufadienolides, as well as for the development of bufadienolide-type drugs with improved pharmacokinetic and safety profiles.
Language英语
Funding OrganizationNational Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; NSF of China ; NSF of China ; Program of Shanghai Academic/Technology Research Leader ; Program of Shanghai Academic/Technology Research Leader ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Education Development Foundation ; Shuguang Program - Shanghai Municipal Education Commission ; Shuguang Program - Shanghai Municipal Education Commission ; Beijing Natural Science Foundation ; Beijing Natural Science Foundation ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; CAMS Innovation Fund for Medical Sciences (CIFMS) ; PUMC Youth Fund ; PUMC Youth Fund ; Fundamental Research Funds for the Central Universities ; Fundamental Research Funds for the Central Universities ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation
WOS IDWOS:000457675500001
PublisherFRONTIERS MEDIA SA
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/166101
Collection中国科学院大连化学物理研究所
Corresponding AuthorGe, Guang-Bo; Sun, Xiao-Bo
Affiliation1.Chinese Acad Med Sci, Inst Med Plant Dev, Minist Educ, Key Lab Bioact Subst & Resources Utilizat Chinese, Beijing, Peoples R China
2.Peking Union Med Coll, Beijing, Peoples R China
3.Dalian Med Univ, Coll Pharm, Dalian, Peoples R China
4.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai, Peoples R China
5.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian, Peoples R China
Recommended Citation
GB/T 7714
Dai, Zi-Ru,Ning, Jing,Sun, Gui-Bo,et al. Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu[J]. FRONTIERS IN PHARMACOLOGY,2019,10:10.
APA Dai, Zi-Ru.,Ning, Jing.,Sun, Gui-Bo.,Wang, Ping.,Zhang, Feng.,...&Yang, Ling.(2019).Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu.FRONTIERS IN PHARMACOLOGY,10,10.
MLA Dai, Zi-Ru,et al."Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu".FRONTIERS IN PHARMACOLOGY 10(2019):10.
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