Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations

doi:10.1124/dmd.112.045641

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	Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations
	Xie, Cen; Zhong, Dafang; Chen, Xiaoyan
刊名	DRUG METABOLISM AND DISPOSITION
	2012-08
卷号	40 期号:8 页码:1628-1640
ISSN号	0090-9556
DOI	10.1124/dmd.112.045641
文献子类	Article
英文摘要	5-O-Caffeoylquinic acid (5-CQA) is one of the major bioactive ingredients in some Chinese herbal injections. Occasional anaphylaxis has been reported for these injections during their clinical use, possibly caused by reactive metabolites of 5-CQA. This study aimed at characterizing the bioactivation pathway(s) of 5-CQA and the metabolic enzyme(s) involved. After incubating 5-CQA with GSH and NADPH-supplemented human liver microsomes, two types of GSH conjugates were characterized: one was M1-1 from the 1,4-addition of GSH to ortho-benzoquinone intermediate; the other was M2-1 and M2-2 from the 1,4-addition of GSH directly to the alpha,beta-unsaturated carbonyl group of the parent. The formation of M1-1 was cytochrome P450 (P450)-mediated, with 3A4 and 2E1 as the principal catalyzing enzymes, whereas the formation of M2-1 and M2-2 was independent of NADPH and could be accelerated by cytosolic glutathione transferase. In the presence of cumene hydroperoxide, M1-1 formation increased 6-fold, indicating that 5-CQA can also be bioactivated by P450 peroxidase under oxidizing conditions. Furthermore, M1-1 could be formed by myeloperoxidase in activated human leukocytes, implying that 5-CQA bioactivation is more likely to occur under inflammatory conditions. This finding was supported by experiments on lipopolysaccharide-induced inflammatory rats, where a greater amount of M1-1 was detected. In S-adenosyl methionine-and GSH-supplemented human S9 incubations, M1-1 formation decreased by 80% but increased after tolcapone-inhibited catechol-O-methyltransferase (COMT) activity. In summary, the high reactivities of the ortho-benzoquinone metabolite and alpha,beta-unsaturated carbonyl group of 5-CQA to nucleophiles have been demonstrated. Different pathological situations and COMT activities in patients may alter the bioactivation extent of 5-CQA.
资助项目	National Natural Science Foundation of China[81173115] ; National Basic Research Program of China[2009CB930300]
WOS关键词	HUMAN LIVER-MICROSOMES ; CHLOROGENIC ACID ; CAFFEIC ACID ; MASS-SPECTROMETRY ; METABOLISM ; ABSORPTION ; CYTOTOXICITY ; ANTIOXIDANT ; CONJUGATION ; GLUTATHIONE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000306496900022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278004]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xie, Cen,Zhong, Dafang,Chen, Xiaoyan. Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations[J]. DRUG METABOLISM AND DISPOSITION,2012,40(8):1628-1640.
APA	Xie, Cen,Zhong, Dafang,&Chen, Xiaoyan.(2012).Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations.DRUG METABOLISM AND DISPOSITION,40(8),1628-1640.
MLA	Xie, Cen,et al."Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations".DRUG METABOLISM AND DISPOSITION 40.8(2012):1628-1640.