Akel Ahmad, Hermle Tobias, Niemoeller Olivier M, Kempe Daniela S, Lang Philipp A, Attanasio Philipp, Podolski Marlis, Wieder Thomas, Lang Florian
Department of Physiology, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany.
Eur J Pharmacol. 2006 Feb 17;532(1-2):11-7. doi: 10.1016/j.ejphar.2005.12.037. Epub 2006 Feb 10.
Side effects of treatment with chlorpromazine include anaemia which could result from decreased formation or accelerated clearance of circulating erythrocytes. Recently, a novel mechanism leading to erythrocyte clearance has been disclosed. Osmotic shock, oxidative stress and glucose deprivation lead to activation of cation channels, Ca(2+) entry, activation of a Ca(2+)-sensitive erythrocyte scramblase and subsequent exposure of phosphatidylserine at the erythrocyte surface. As macrophages are equipped with phosphatidylserine receptors, they bind, engulf and degrade phosphatidylserine exposing cells. The present experiments have been performed to explore whether chlorpromazine triggers phosphatidylserine exposure of erythrocytes. The phosphatidylserine exposure was estimated from annexin binding as determined in fluorescence activated cell sort (FACS) analysis. A 24 h exposure to glucose-free medium decreased cytosolic ATP levels, decreased cellular levels of reduced glutathione (GSH) and increased annexin binding. The effect on annexin binding and ATP but not on GSH was significantly enhanced in the presence of chlorpromazine (10 microM). Higher concentrations of chlorpromazine (40 microM) increased cytosolic Ca(2+) activity. Osmotic shock and Cl(-) removal similarly increased annexin binding, effects again being enhanced in the presence of chlorpromazine. In conclusion, the present observations point to a novel side effect of chlorpromazine, i.e. increased sensitivity of erythrocytes to glucose deprivation. The effect could well contribute to the known anaemia observed in the treatment with this antipsychotic drug.
氯丙嗪治疗的副作用包括贫血，这可能是由于循环红细胞生成减少或清除加速所致。最近，一种导致红细胞清除的新机制已被揭示。渗透休克、氧化应激和葡萄糖剥夺会导致阳离子通道激活、钙离子内流、钙敏感的红细胞翻转酶激活，随后红细胞表面暴露磷脂酰丝氨酸。由于巨噬细胞配备有磷脂酰丝氨酸受体，它们会结合、吞噬并降解暴露磷脂酰丝氨酸的细胞。进行本实验是为了探究氯丙嗪是否会引发红细胞磷脂酰丝氨酸的暴露。通过荧光激活细胞分选（FACS）分析中测定的膜联蛋白结合来估计磷脂酰丝氨酸的暴露情况。暴露于无葡萄糖培养基24小时会降低胞质ATP水平，降低细胞内还原型谷胱甘肽（GSH）水平，并增加膜联蛋白结合。在氯丙嗪（10微摩尔）存在的情况下，对膜联蛋白结合和ATP的影响显著增强，但对GSH的影响未增强。更高浓度的氯丙嗪（40微摩尔）会增加胞质钙离子活性。渗透休克和去除氯离子同样会增加膜联蛋白结合，在氯丙嗪存在时这些影响再次增强。总之，目前的观察结果表明氯丙嗪有一个新的副作用，即红细胞对葡萄糖剥夺的敏感性增加。这种作用很可能导致在用这种抗精神病药物治疗时出现已知的贫血。
