Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations
Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations
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5-O-咖啡酰奎宁酸邻苯醌中间体的体外和体内鉴定：正常和病理情况下生物活性的比较
DOI：
10.1124/dmd.112.045641
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发表时间：
2012-08
影响因子：
3.9
通讯作者：
Chen, Xiaoyan
中科院分区：
文献类型：
--
作者：
Xie, Cen;Zhong, Dafang;Chen, Xiaoyan
5-O-咖啡酰奎宁酸(5-CQA)是一些中草药注射剂的主要活性成分之一。据报道，这些注射剂在临床使用过程中偶尔会出现过敏反应，可能是由5-CQA的反应性代谢物引起的。本研究旨在研究5-氯喹酮的生物活化途径(S)及其所涉及的代谢酶(S)。将5-CQA与谷胱甘肽和添加NADPH的人肝微粒体孵育后，鉴定了两种类型的谷胱甘肽结合物：一种是谷胱甘肽与邻苯二酚中间体1，4-加成而成的M1-1，另一种是由谷胱甘肽直接加成到母体α，β-不饱和羰基上的M2-1和M2-2。M1-1的形成是由细胞色素P450(P450)介导的，3A4和2E1是主要的催化酶，而M2-1和M2-2的形成不受NADPH的影响，可被胞质谷胱甘肽转移酶加速。在过氧化异丙苯存在下，M1-1生成量增加了6倍，表明在氧化条件下，5-CQA也能被P450过氧化物酶激活。此外，在激活的人白细胞中，髓过氧化物酶可以形成M1-1，这意味着在炎症条件下更有可能发生5-CQA的生物激活。这一发现得到了内毒素诱导的炎症大鼠实验的支持，在这些实验中检测到了更多的M1-1。在添加了腺苷蛋氨酸和谷胱甘肽的人S9细胞中，M1-1的形成减少了80%，但在Tolcapone抑制儿茶酚-O-甲基转移酶的活性后，M1-1的形成增加。综上所述，5-氯喹酮的邻苯二酚代谢物和α，β-不饱和羰基对亲核剂具有很高的反应性。患者不同的病理状态和COMT活性可能会改变5-CQA的生物激活程度。
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 α,β-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 α,β-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.
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影响因子：
64.8
作者：
FREEDMAN, SO;KRUPEY, J;SEHON, AH
通讯作者：
SEHON, AH
影响因子：
5.2
作者：
Dupas, Coralie;Baglieri, Agnes Marsset;Maillard, Marie-Noelle
通讯作者：
Maillard, Marie-Noelle
影响因子：
5.8
作者：
Rodrigues Ad
通讯作者：
Rodrigues Ad
DOI：
--
发表时间：
2008
期刊：
Modern Medicine Health
影响因子：
--
作者：
Z. Hong
通讯作者：
Z. Hong
影响因子：
--
作者：
R. Hurrell;P. Finot
通讯作者：
R. Hurrell;P. Finot