Lai W G, Zahid N, Uetrecht J P
Faculties of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
J Pharmacol Exp Ther. 1999 Oct;291(1):292-9.
The antibacterial agent, trimethoprim, is normally used synergistically with sulfonamides. Its use is associated with idiosyncratic reactions including liver toxicity and agranulocytosis. In this study, we demonstrated that trimethoprim was oxidized by activated human neutrophils, as well as a combination of myeloperoxidase/hydrogen peroxide/chloride or hypochlorous acid, to a reactive pyrimidine iminoquinone methide intermediate with a protonated molecular ion of m/z 289 as detected by mass spectrometry. In the presence of N-acetyl-L-cysteine (NAC), the pyrimidine iminoquinone methide could be trapped as three NAC adducts. The three NAC adducts were separable on HPLC, but showed the same protonated molecular ion of m/z 452. The proton NMR spectrum of the major adduct showed that the NAC group was at the 6 position of the pyrimidine ring. The mass spectra of the two minor NAC adducts indicated that they were the two diastereomers in which NAC was attached to the exo-cyclic prechiral carbon of the pyrimidine iminoquinone methide. Incubation of trimethoprim with isolated hepatic microsomes, both human and rat, in presence of NAC gave the same set of trimethoprim-NAC adducts. We propose that the formation of this pyrimidine iminoquinone methide by both hepatic microsomes and neutrophils may be responsible for trimethoprim-induced idiosyncratic hepatotoxicity and agranulocytosis.
抗菌剂甲氧苄啶通常与磺胺类药物协同使用。其使用与特异反应有关，包括肝毒性和粒细胞缺乏症。在本研究中，我们证明甲氧苄啶可被活化的人中性粒细胞以及髓过氧化物酶/过氧化氢/氯化物或次氯酸的组合氧化，形成一种反应性嘧啶亚氨基醌甲基化物中间体，通过质谱检测其质子化分子离子的质荷比为m/z 289。在N-乙酰-L-半胱氨酸（NAC）存在下，嘧啶亚氨基醌甲基化物可被捕获为三种NAC加合物。这三种NAC加合物在高效液相色谱上可分离，但显示相同的质子化分子离子，质荷比为m/z 452。主要加合物的质子核磁共振谱表明NAC基团位于嘧啶环的6位。两种次要NAC加合物的质谱表明它们是两种非对映异构体，其中NAC连接到嘧啶亚氨基醌甲基化物的环外前手性碳上。在NAC存在下，将甲氧苄啶与人及大鼠的分离肝微粒体一起孵育，得到相同的一组甲氧苄啶-NAC加合物。我们认为肝微粒体和中性粒细胞形成这种嘧啶亚氨基醌甲基化物可能是甲氧苄啶引起特异质性肝毒性和粒细胞缺乏症的原因。
