Erve John C L, Svensson Mats A, von Euler-Chelpin Hans, Klasson-Wehler Eva
Departments of DMPK & Bioanalytical Chemistry and Computational Chemistry, AstraZeneca R&D, S-151 85 Södertälje, Sweden.
Chem Res Toxicol. 2004 Apr;17(4):564-71. doi: 10.1021/tx034238n.
Remoxipride is an atypical antipsychotic displaying selective binding to the dopamine D2 receptor. Several cases of aplastic anemia led to the withdrawal of remoxipride from the market in December 1993. The remoxipride metabolite NCQ-344 is a hydroquinone while the structural isomer NCQ-436 is a catechol, both of which have been suggested to be capable of forming a reactive para- and ortho-quinone, respectively. Recently, these two remoxipride metabolites were shown to induce apoptosis in human bone marrow progenitor cells. Furthermore, NCQ-344 also caused necrosis of these cells unlike NCQ-436. Although NCQ-344 has been detected in plasma of humans dosed with remoxipride, to date, no experimental evidence for the formation of the corresponding para-quinone has been obtained. Here, we report the detection of three glutathione (GSH) conjugates of NCQ-344 in vitro that were formed following a chemical reaction and characterized by tandem mass spectrometry and for a cyclized conjugate additionally with derivatization and deuterium exchange. In contrast, NCQ-436 did not form a GSH conjugate. Hypochlorous acid oxidized NCQ-344 to the para-quinone while NCQ-436 was resistant to oxidation. Upon incubation with NCQ-344, stimulated human neutrophils produced from 2- to 5-fold greater amounts of glutathione conjugates than unstimulated neutrophils. Ab initio calculations on these remoxipride metabolites indicated that the reaction leading to the respective quinone was spontaneous for the para-quinone (e.g., from NCQ-344) while ortho-quinone (e.g., from NCQ-436) formation was not. These results demonstrate that NCQ-344 is capable of facile formation of a reactive para-quinone capable of reacting with GSH and may rationalize previous findings regarding the biological effects observed in vitro with these two remoxipride metabolites.
瑞莫必利是一种非典型抗精神病药物，对多巴胺D2受体具有选择性结合作用。1993年12月，几例再生障碍性贫血病例导致瑞莫必利退出市场。瑞莫必利代谢产物NCQ - 344是一种对苯二酚，而结构异构体NCQ - 436是一种儿茶酚，二者均被认为分别能够形成反应性对醌和邻醌。最近，这两种瑞莫必利代谢产物被证明可诱导人骨髓祖细胞凋亡。此外，与NCQ - 436不同，NCQ - 344还会导致这些细胞坏死。虽然在服用瑞莫必利的人的血浆中检测到了NCQ - 344，但迄今为止，尚未获得形成相应对醌的实验证据。在此，我们报告在体外检测到NCQ - 344的三种谷胱甘肽（GSH）结合物，这些结合物是通过化学反应形成的，并通过串联质谱进行了表征，对于一种环化结合物还进行了衍生化和氘交换。相比之下，NCQ - 436未形成GSH结合物。次氯酸将NCQ - 344氧化为对醌，而NCQ - 436对氧化具有抗性。与NCQ - 344孵育后，受刺激的人中性粒细胞产生的谷胱甘肽结合物比未受刺激的中性粒细胞多2至5倍。对这些瑞莫必利代谢产物的从头算计算表明，导致相应醌形成的反应对对醌（例如，来自NCQ - 344）是自发的，而邻醌（例如，来自NCQ - 436）的形成则不是。这些结果表明，NCQ - 344能够轻易形成一种能够与GSH反应的反应性对醌，这可能解释了先前关于这两种瑞莫必利代谢产物在体外观察到的生物学效应的研究结果。
