McMillan D C, Jensen C B, Jollow D J
Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Pharmacol Exp Ther. 1998 Dec;287(3):868-76.
Dapsone hydroxylamine (DDS-NOH) is a direct-acting hemolytic agent responsible for dapsone-induced hemolytic anemia in the rat. The hemolytic activity of DDS-NOH is associated with the formation of disulfide-linked hemoglobin adducts on membrane skeletal proteins. We have postulated that this membrane protein "damage" is a consequence of DDS-NOH-induced oxidative stress within the red cell and that it serves as the trigger for premature removal of injured but intact red cells from the circulation by splenic macrophages. Oxidative stress has also been associated with the induction of lipid peroxidation, and it is possible that direct damage to the lipoidal membrane may play a role in the premature sequestration of the damaged cells in the spleen. To investigate this possibility, rat and human red cells were incubated with hemolytic concentrations of DDS-NOH and examined for evidence of lipid peroxidation using two independent assays: thiobarbituric acid-reactive substances formation and cis-paranaric acid degradation. Phenylhydrazine, which is known to induce lipid peroxidation in red cells, was used as a positive control. The extent of thiobarbituric acid-reactive substances formation and cis-paranaric acid degradation in DDS-NOH-treated rat and human red cells was not significantly different from that in control cells. In contrast, thiobarbituric acid-reactive substances formation and cis-paranaric acid degradation were significantly increased in red cells treated with hemolytic concentrations of the positive control, phenylhydrazine. These data suggest that lipid peroxidation is not involved in the mechanism underlying dapsone-induced hemolytic anemia.
氨苯砜羟胺（DDS-NOH）是一种直接作用的溶血剂，可导致大鼠发生氨苯砜诱导的溶血性贫血。DDS-NOH的溶血活性与膜骨架蛋白上二硫键连接的血红蛋白加合物的形成有关。我们推测这种膜蛋白“损伤”是红细胞内DDS-NOH诱导的氧化应激的结果，并且它是脾脏巨噬细胞将受损但完整的红细胞从循环中过早清除的触发因素。氧化应激也与脂质过氧化的诱导有关，脂质膜的直接损伤可能在脾脏中受损细胞的过早隔离中起作用。为了研究这种可能性，将大鼠和人类红细胞与溶血浓度的DDS-NOH孵育，并使用两种独立的测定方法检测脂质过氧化的证据：硫代巴比妥酸反应性物质的形成和顺式对氧萘甲酸的降解。已知能诱导红细胞脂质过氧化的苯肼用作阳性对照。在DDS-NOH处理的大鼠和人类红细胞中，硫代巴比妥酸反应性物质的形成和顺式对氧萘甲酸的降解程度与对照细胞中的无显著差异。相比之下，用溶血浓度的阳性对照苯肼处理的红细胞中，硫代巴比妥酸反应性物质的形成和顺式对氧萘甲酸的降解显著增加。这些数据表明脂质过氧化不参与氨苯砜诱导的溶血性贫血的潜在机制。
