Gutierrez P L, Siva S
University of Maryland Cancer Center, Baltimore 21201, USA.
Chem Res Toxicol. 1995 Apr-May;8(3):455-64. doi: 10.1021/tx00045a018.
The antitumor agent diaziquone (AZQ) reacts with reduced glutathione (GSH) in aqueous solutions and under aerobic conditions to give rise to the glutathionyl and hydroxyl free radicals, as well as the AZQ semiquinone. Under anaerobic conditions, the only radical observed was the glutathionyl radical. These radicals are quickly abrogated when superoxide dismutase and catalase are coincubated. Separately, superoxide dismutase favors the formation of thiyl radicals while catalase favors the formation of hydroxyl radicals and AZQ semiquinone. The metal chelator diethylenetriaminepentaacetic acid favors the production of hydroxyl radicals and AZQ semiquinone. The reaction of AZQ with GSH at pH 7.2 and 5.5 results in a variety of conjugates. These conjugates include addition of glutathione to both aziridines, displacement of the aziridines by GSH, and a combination of both. The majority of the conjugates are formed by nucleophilic attack of GSH to the AZQ aziridines or by 1,4-Michael addition to the AZQ quinone or a combination of both. There may be a small free radical component in conjugate formation, but the majority of the free radicals observed are from redox reactions that involve the oxidation of glutathione and the reduction and autoxidation of AZQ to produce oxygen radicals and hydrogen peroxide, a process that is enhanced by trace metal ions.
抗肿瘤药物重氮醌（AZQ）在水溶液中且有氧条件下与还原型谷胱甘肽（GSH）反应，生成谷胱甘肽基自由基和羟基自由基以及AZQ半醌自由基。在厌氧条件下，观察到的唯一自由基是谷胱甘肽基自由基。当超氧化物歧化酶和过氧化氢酶共同孵育时，这些自由基会迅速消除。单独来看，超氧化物歧化酶有利于硫自由基的形成，而过氧化氢酶有利于羟基自由基和AZQ半醌自由基的形成。金属螯合剂二乙烯三胺五乙酸有利于羟基自由基和AZQ半醌自由基的产生。AZQ与GSH在pH 7.2和5.5条件下反应会产生多种共轭物。这些共轭物包括谷胱甘肽与两个氮丙啶环的加成、谷胱甘肽取代氮丙啶环以及两者的结合。大多数共轭物是由谷胱甘肽对AZQ氮丙啶环的亲核攻击或对AZQ醌的1,4 - 迈克尔加成或两者结合形成的。共轭物形成过程中可能存在少量自由基成分，但观察到的大多数自由基来自涉及谷胱甘肽氧化以及AZQ还原和自氧化以产生氧自由基和过氧化氢的氧化还原反应，微量金属离子会增强这一过程。
