Ring addition of the alpha-amino group of glutathione increases the reactivity of benzoquinone thioethers.
2-(Glutathion-S-yl)-1,4-benzoquinone was found to be remarkably unstable in phosphate buffer (pH 7.4) even in the absence of oxygen. Intramolecular addition of the alpha-amino group of the glutamate residue to the quinone ring yielded ultimately 2,3-(glutathion-N, S-yl)-1,4-benzoquinone and 2,6-(glutathion-N,S-yl)-1,4-benzoquinone in a 3:1 ratio along with 2-(glutathion-S-yl)-1,4-hydroquinone. Kinetic studies indicated that the cyclization reactions proceeded at a rate k1 of 0.093 min-1, while intermolecular reactions followed a second-order kinetics with a k2 of 94 M-1 min-1 (pH 7.4, 37 degreesC), resulting in multiple polymerization products. Both intramolecular amino adducts of 2-(glutathion-S-yl)-1,4-benzoquinone are prone to hydrolysis, leading to the insertion of an additional OH group in the ring. These S-substituted trihydroxybenzene derivatives are particularly susceptible to autoxidation. The model compound 6-(N-acetylcystein-S-yl)-2-hydroxy-1,4-hydroquinone was shown to form readily two atropoisomeric biphenyls upon autoxidation: 2,4'-bis(N-acetylcystein-S-yl)-2',3,3',4,6, 6'-hexahydroxybiphenyl, indicating C-C coupling, presumably via semiquinone radical intermediates. Thus, the sequence of glutathione S-addition, followed by oxidation, N-addition, oxidation, and hydrolysis, constitutes a novel and very effective activation pathway of quinones for eliciting oxidative stress. These data underline the fact that glutathione conjugates of autoxidizable aromatics are no obligatory stable end products of a detoxication reaction. The possible toxicological impacts of intra- and intermolecular addition reactions of quinoid thiol conjugates are discussed.
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Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Nussbaumstrasse 26, D-80336 München, Germany.
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D000111:Acetylcysteine / Q000378:metabolism; D016227:Benzoquinones / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction
D016227:Benzoquinones; C004532:quinone; D005978:Glutathione; D000111:Acetylcysteine