Cytochrome p450 3a enzymes are key contributors for hepatic metabolism of bufotalin, a natural constitute in chinese medicine chansu
文献类型：期刊论文
| 作者 | 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 |
| 刊名 | Frontiers in pharmacology
 |
| 出版日期 | 2019-02-04 |
| 卷号 | 10页码:10 |
| ISSN号 | 1663-9812 |
| 关键词 | Bufotalin Cytochrome p450 3a (cyp3a) Hydroxylation Human liver microsomes (hlms) Docking simulations |
| DOI | 10.3389/fphar.2019.00052 |
| 通讯作者 | Ge, guang-bo(geguangbo@dicp.ac.cn) ; Sun, xiao-bo(sun_xiaobo@163.com) |
| 英文摘要 | Bufotalin (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. |
| WOS关键词 | PHASE-I METABOLISM ; ISOFORM-SPECIFIC PROBE ; HUMAN LIVER-MICROSOMES ; DRUG-DRUG INTERACTION ; CYTOTOXIC BUFADIENOLIDES ; ACTIVE-SITE ; VITRO ; BINDING ; BUFALIN ; HYDROXYLATION |
| WOS研究方向 | Pharmacology & Pharmacy |
| WOS类目 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | FRONTIERS MEDIA SA |
| WOS记录号 | WOS:000457675500001 |
| URI标识 | http://www.irgrid.ac.cn/handle/1471x/2372817 |
| 专题 | 大连化学物理研究所 |
| 通讯作者 | Ge, Guang-Bo; Sun, Xiao-Bo |
| 作者单位 | 1.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 |
| 推荐引用方式 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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来源：大连化学物理研究所
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