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题名: Characterization of human cytochrome P450 isoforms involved in the metabolism of 7-epi-paclitaxel
作者: Zhang, Y. -Y.1, 3;  Liu, Y.1;  Zhang, J. -W.1;  Ge, G. -B.1;  Wang, L. -M.2;  Sun, J.2;  Yang, L.1
通讯作者: 杨凌
关键词: 7-Epi-paclitaxel ;  paclitaxel ;  cytochrome P450 ;  microsomes ;  metabolism
刊名: XENOBIOTICA
发表日期: 2009
DOI: 10.1080/00498250802714907
卷: 39, 期:4, 页:283-292
收录类别: SCI
文章类型: Article
部门归属: 18
项目归属: 1806
产权排名: 1;1
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy ;  Toxicology
研究领域[WOS]: Pharmacology & Pharmacy ;  Toxicology
英文摘要: The C-7 chiral centre in paclitaxel is subject to epimerization under physiological conditions, thus making 7-epi-paclitaxel as the principal degradant. This study was designed to characterize the cytochrome P450 (CYP) enzymes involved in 7-epi-paclitaxel metabolism, and to examine possible metabolic interactions that this C-7 epimer may have with paclitaxel. In human liver microsomes, 7-epi-paclitaxel was oxidized to two monohydroxylated metabolites while the metabolic sites occurred at the C-13 side-chain for M-1 and taxane core ring for M-2. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs, and enzyme kinetics indicated that M-1 was generated predominantly by CYP3A4 and M-2 by CYP2C8. Co-incubation of 7-epi-paclitaxel with paclitaxel in human liver microsomes resulted in potent inhibition of 6-hydroxypaclitaxel formation (IC50 = 2.1 0.2 M), thus decreasing the metabolic elimination of paclitaxel. In conclusion, both CYP3A4 and CYP2C8 play a major role in biotransformation of 7-epi-paclitaxel in human liver microsomes. The existence of epimeric interactions between paclitaxel and its degradant might be a noteworthy factor resulting in the complex pharmacokinetic profile of paclitaxel.
关键词[WOS]: IONIZATION MASS-SPECTROMETRY ;  HUMAN LIVER-MICROSOMES ;  IN-VITRO METABOLISM ;  LIQUID-CHROMATOGRAPHY ;  REGIOSELECTIVE METABOLISM ;  TAXOL METABOLISM ;  PACLITAXEL ;  IDENTIFICATION ;  TAXANES ;  CANCER
语种: 英语
原文出处: 查看原文
WOS记录号: WOS:000265303000001
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/101607
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.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China
2.Dalian Med Univ, Affiliated Hosp 2, Dalian, Peoples R China
3.Chinese Acad Sci, Grad Sch, Beijing, Peoples R China

Recommended Citation:
Zhang, Y. -Y.,Liu, Y.,Zhang, J. -W.,et al. Characterization of human cytochrome P450 isoforms involved in the metabolism of 7-epi-paclitaxel[J]. XENOBIOTICA,2009,39(4):283-292.
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