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学科主题: 物理化学
题名: Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human
作者: Ma, Xiao-Chi1, 2;  Ning, Jing1, 2;  Ge, Guang-Bo1;  Liang, Si-Cheng1;  Wang, Xiu-Li1;  Zhang, Bao-Jing2;  Huang, Shan-Shan2;  Li, Jing-Kui2;  Yang, Ling1
通讯作者: 杨凌
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2011-04-01
DOI: 10.1124/dmd.110.036830
卷: 39, 期:4, 页:675-682
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
摘要: Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Cinobufagin (CB), a major bioactive component of the traditional Chinese medicine Chansu, has been reported to have potent antitumor activity. In this study, in vitro metabolism of CB among species was compared with respect to metabolic profiles, enzymes involved, and catalytic efficiency by using liver microsomes from human (HLM), mouse (MLM), rat (RLM), dog (DLM), minipig (PLM), and monkey (CyLM). Significant species differences in CB metabolism were revealed. In particular, species-specific deacetylation and epimerization combined with hydroxylation existed in RLM, whereas hydroxylation was a major pathway in HLM, MLM, DLM, PLM, and CyLM. Two monohydroxylated metabolites of CB in human and animal species were identified as 1 alpha-hydroxylcinobufagin and 5 beta-hydroxylcinobufagin by using liquid chromatography-mass spectrometry and two-dimensional NMR techniques. CYP3A4 was identified as the main isoform involved in CB hydroxylation in HLM on the basis of the chemical inhibition studies and screen assays with recombinant human cytochrome P450s. Furthermore, ketoconazole, a specific inhibitor of CYP3A, strongly inhibited CB hydroxylation in MLM, DLM, PLM, and CyLM, indicating that CYP3A was responsible for CB hydroxylation in these animal species. The apparent substrate affinity and catalytic efficiency for 1 alpha- and 5 beta-hydroxylation of CB in liver microsomes from various species were also determined. PLM appears to have Km and total intrinsic clearance value (V(max)/K(m)) similar to those for HLM, and the total microsomal intrinsic clearance values for CB obeyed the following order: mouse > dog > monkey > human > minipig. These findings provide vital information to better understand the metabolic behaviors of CB among various species.
关键词[WOS]: PERFORMANCE LIQUID-CHROMATOGRAPHY ;  TRADITIONAL CHINESE MEDICINE ;  HUMAN CYTOCHROME-P450 3A4 ;  TOAD VENOM ;  IN-VITRO ;  CHAN-SU ;  MASS-SPECTROMETRY ;  DRUG-METABOLISM ;  BUFADIENOLIDES ;  INHIBITION
语种: 英语
WOS记录号: WOS:000288424400013
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/115812
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, Sch Pharmaceut Sci, Dalian, Peoples R China

Recommended Citation:
Ma, Xiao-Chi,Ning, Jing,Ge, Guang-Bo,et al. Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human[J]. DRUG METABOLISM AND DISPOSITION,2011,39(4):675-682.
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