Müller K, Gürster D
Institute of Pharmacy, University of Regensburg, Germany.
Biochem Pharmacol. 1993 Nov 17;46(10):1695-704. doi: 10.1016/0006-2952(93)90573-f.
The antipsoriatic anthrones anthralin and butantrone caused degradation of the DNA sugar deoxyribose in the presence of ferric salt. The degradation was substantially inhibited by iron-binding hydroxyl radical scavengers, iron chelators, superoxide dismutase (SOD) and catalase, suggesting a mechanism in which antipsoriatic anthrones generate hydroxyl radicals via the Fenton reaction or an iron-catalysed Haber-Weiss reaction. Butantrone was markedly less efficient at generating hydroxyl radicals than anthralin. Using bovine brain phospholipid liposomes as model membranes to study the effects of antipsoriatic anthrones on lipid peroxidation, the peroxidation of liposomal membranes in the presence of ferric salt was maximally enhanced by anthralin and butantrone at 12.5 and 5 microM, respectively. Higher concentrations of the drugs resulted in less peroxidation. Chain-breaking antioxidants and iron chelators strongly decreased anthralin-enhanced lipid peroxidation, suggesting the involvement of hydroxyl, peroxyl or alkoxyl radicals. In contrast to their stimulatory effects on liposomal membrane peroxidation, both anthralin and butantrone diminished Fe3+/ascorbate-induced lipid peroxidation in liposomes. Butantrone was more effective as an inhibitor of lipid peroxidation than was anthralin. The antioxidant properties of antipsoriatic anthrones were determined in terms of their reactivities with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). Antioxidant activity of antipsoriatic anthrones requires the presence of free hydroxyl groups at C-1 and C-8 and at least one hydrogen atom at C-10 of the anthrone nucleus. The role of active oxygen species produced by antipsoriatic anthrones and the biological effects on cellular targets are discussed with respect to the mode of action and manifestation of side effects of these drugs.
抗银屑病蒽酮类药物蒽林和丁酮在铁盐存在的情况下会导致DNA糖脱氧核糖降解。铁结合型羟基自由基清除剂、铁螯合剂、超氧化物歧化酶（SOD）和过氧化氢酶可显著抑制这种降解，这表明抗银屑病蒽酮类药物通过芬顿反应或铁催化的哈伯-维伊斯反应产生羟基自由基的机制。在产生羟基自由基方面，丁酮的效率明显低于蒽林。使用牛脑磷脂脂质体作为模型膜来研究抗银屑病蒽酮类药物对脂质过氧化的影响，在铁盐存在的情况下，蒽林和丁酮分别在12.5微摩尔和5微摩尔时最大程度地增强了脂质体膜的过氧化。药物浓度更高时，过氧化程度降低。链断裂抗氧化剂和铁螯合剂强烈降低了蒽林增强的脂质过氧化，表明涉及羟基、过氧自由基或烷氧自由基。与它们对脂质体膜过氧化的刺激作用相反，蒽林和丁酮都减少了脂质体中Fe3+/抗坏血酸诱导的脂质过氧化。作为脂质过氧化抑制剂，丁酮比蒽林更有效。根据抗银屑病蒽酮类药物与稳定自由基2,2-二苯基-1-苦基肼（DPPH）的反应性来确定其抗氧化性能。抗银屑病蒽酮类药物的抗氧化活性需要在蒽酮核的C-1和C-8处存在游离羟基以及在C-10处至少有一个氢原子。就这些药物的作用方式和副作用表现，讨论了抗银屑病蒽酮类药物产生的活性氧的作用及其对细胞靶点的生物学效应。
