Identification of Quinone Methide Metabolites of Dauricine in Human Liver Microsomes and in Rat Bile

doi:10.1021/tx800397e

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	Identification of Quinone Methide Metabolites of Dauricine in Human Liver Microsomes and in Rat Bile
	Wang, Yuya 2; Zhong, Dafang2 ; Chen, Xiaoyan2 ; Zheng, Jiang 1
刊名	CHEMICAL RESEARCH IN TOXICOLOGY
	2009-05
卷号	22 期号:5 页码:824-834
ISSN号	0893-228X
DOI	10.1021/tx800397e
文献子类	Article
英文摘要	Dauricine is one type of the bisbenzyltetrahydroisoquinoline alkaloid derivative with antiarrhythmic effects. Severe liver toxicity was observed in experimental animals treated with analogues of dauricine, which may be caused by covalent binding of reactive metabolite(s) to critical macromolecules in tissues. The study described herein aimed at characterizing pathways of dauricine bioactivation and the CYP enzyme involved. In incubations of dauricine with NADPH- and GSH-supplemented human liver microsomes, four GSH conjugates with [M + H](+) ions at m/z 930, 916, 916, and 902, respectively, were detected by liquid chromatography-ion trap mass spectrometry. The structures of the four metabolites were determined to be GSH conjugates of dauricine, 2-N-demethyl dauricine, 2'-N-demethyl dauricine, and N-demethyl-O-demethyl dauricine. GSH conjugation took place with a strong preference at C-17, suggesting that the phenol moiety of dauricine and its metabolites underwent oxidation to quinone methide intermediates. The formation of the GSH conjugates was found to require the presence of NADPH. To identify the CYP isoforms that are responsible for bioactivation, dauricine was also incubated with recombinant human CYP450 enzymes. The formation of GSH was only observed with the incubation of CYP3A4. In addition, the level of these GSH conjugates in human microsomes was reduced upon the addition of a CYP3A4 inhibitor ketoconazole. The same GSH conjugates were also observed in rat bile following a single oral dose of 40 mg/kg dauricine. These studies suggest that the CYP3A4 mediated quinone methide formation was associated with dauricine bioactivation.
资助项目	National Natural Science Foundation of China[30873119]
WOS关键词	TOPOISOMERASE-II POISON ; BISBENZYLISOQUINOLINE ALKALOIDS ; CYTOTOXIC ACTIVITIES ; TETRANDRINE
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Toxicology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000266201200010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279249]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	1.Univ Washington, Ctr Dev Therapeut, Seattle Childrens Hosp Res Inst, Div Gastroenterol,Dept Pediat, Seattle, WA 98195 USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China;
推荐引用方式 GB/T 7714	Wang, Yuya,Zhong, Dafang,Chen, Xiaoyan,et al. Identification of Quinone Methide Metabolites of Dauricine in Human Liver Microsomes and in Rat Bile[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2009,22(5):824-834.
APA	Wang, Yuya,Zhong, Dafang,Chen, Xiaoyan,&Zheng, Jiang.(2009).Identification of Quinone Methide Metabolites of Dauricine in Human Liver Microsomes and in Rat Bile.CHEMICAL RESEARCH IN TOXICOLOGY,22(5),824-834.
MLA	Wang, Yuya,et al."Identification of Quinone Methide Metabolites of Dauricine in Human Liver Microsomes and in Rat Bile".CHEMICAL RESEARCH IN TOXICOLOGY 22.5(2009):824-834.