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题名: Taxane's substituents at C3 ' affect its regioselective metabolism: Different in vitro metabolism of cephalomannine and paclitaxel
作者: Zhang, Jiang-Wei1, 4;  Ge, Guang-Bo1, 4;  Liu, Yong1;  Wang, Li-Ming3;  Liu, Xing-Bao1;  Zhang, Yan-Yan1, 4;  Li, Wei1, 4;  He, Yu-Qi5;  Wang, Zheng-Tao5;  Sun, Jie3;  Xiao, Hong-Bin2;  Yang, Ling1
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2008-02-01
DOI: 10.1124/dmd.107.018242
卷: 36, 期:2, 页:418-426
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: To investigate how taxane's substituents at C3' affect its metabolism, we compared the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3' position. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/ tandem mass spectrometry. C4 '' (M1) and C6 alpha (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by H-1 NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4-hydroxycephalomannine was generated predominantly by CYP3A4 and 6 alpha-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6 alpha for paclitaxel and cephalomannine varied significantly (15: 85 vs. 64: 36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6 alpha to C4 '', and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4 ''- hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4 ''-hydroxylation, whereas paclitaxel adopted an orientation favoring 3'-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased V-m. Our results demonstrate that relatively minor modification of taxane at C3' has major consequence on the metabolism.
关键词[WOS]: TANDEM MASS-SPECTROMETRY ;  LIVER-MICROSOMES ;  PHASE-I ;  CYTOCHROME-P450 3A4 ;  DRUG-INTERACTIONS ;  SOLID TUMORS ;  TAXOL ;  ISOFORMS ;  ANALOGS ;  RAT
语种: 英语
WOS记录号: WOS:000252634900026
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141166
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 Pharmceut Resource Discovery, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Med Chem Lab, Dalian, Peoples R China
3.Dalian Med Univ, Affliated Hosp 2, Dalian, Peoples R China
4.Chinese Acad Sci, Grad Sch, Beijing, Peoples R China
5.Shanghai Univ Tradit Chinese Med Med, Shanghai, Peoples R China

Recommended Citation:
Zhang, Jiang-Wei,Ge, Guang-Bo,Liu, Yong,et al. Taxane's substituents at C3 ' affect its regioselective metabolism: Different in vitro metabolism of cephalomannine and paclitaxel[J]. DRUG METABOLISM AND DISPOSITION,2008,36(2):418-426.
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