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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, Pig, Monkey and Human
作者: Ning J(宁静) ;  Ge GB(葛广波) ;  Ma XC(马骁驰) ;  Liang SC(梁思成) ;  Yang L(杨凌)
会议名称: 18th International Symposium on Microsomes and Drug Oxidations
会议日期: 2010-5-17
出版日期: 2010-05-17
会议地点: 中国
通讯作者: 杨凌
主办者: 国际异物质研究学会
摘要: Cinobufagin (CBG), a major bioactive component of Traditional Chinese Medicine ChanSu with digoxin-like structure, has been reported with Na+-K+-ATPase inhibitory effects and outstanding antitumor activities. In this study, a comparative study on the in vitro metabolic of CBG was first carried out by using liver microsomes from human and five common experimental animals, including mouse, rat, dog, pig and monkey. The results showed significant species differences in both metabolic pathways and hepatic clearances of CBG between human and rat. The species-specific deacetylation of CBG was found as a major in vitro metabolic pathway in rat, while two mono-hydroxylated metabolites of CBG were also detected. In sharp contrast, hydroxylation of CBG was the major in vitro metabolic pathway in human, mouse, dog, pig and monkey. Two mono-hydroxylated metabolites of CBG in human and other animal species were identified as C-5 and C-12 mono-hydroxylated metabolites by using LC–MS, 1H-NMR and 13C-NMR. A combination of chemical inhibition studies and assays with recombinant human CYPs confirmed that CYP3A4 was the main isoform for hydroxylation of CBG. Furthermore, two inhibitors of CYP3A (ketoconazole and troleandomycin) can strongly inhibit the hydroxylation of CBG in mouse, dog, pig and monkey, indicating CYP3A involved in hydroxylation of CBG in all above species. Kinetic studies showed that CBG can be rapid hydrolyzed by esterase in rat liver microsomes, with the Km and Vmax values were 32.85 µM and 15.77 nmol/min/mg protein, respectively. The kinetic parameters and catalytic efficiency of CBG hydroxylations by liver microsomes from various experimental animals were also determined. The intrinsic clearances (Vmax/ Km) for both C-5 and C-12 hydroxylation of CBG in liver microsomes among various species obey the following sequence, Mouse > Dog > Monkey > Minipig > Human. In summary, the in vitro metabolic pathways of CBG in human and various animal species were revealed and our results strongly suggest that rat could not serve as surrogate models for human in toxic and pharmacokinetic studies of CBG. The comparative study on the in vitro metabolic also provided vital information for understanding the pharmacokinetic behaviors of CBG containing Chinese Traditional Medicines.
语种: 中文
内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/114178
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Ning J,Ge GB,Ma XC,et al. Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Pig, Monkey and Human[C]. 见:18th International Symposium on Microsomes and Drug Oxidations. 中国. 2010-5-17.
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