Peroxidation of lipids in liposomal membranes of different composition photosensitized by chlorpromazine

摘要

Chlorpromazine(CPZ),a phenothiazine derivative,is a neuroleptic drug widely used in medicine because of its tranquilizing and antipsychotic properties.CPZ often causes side effects including cutaneous photosensitization and ocular damage.It was suggested that reactive oxygen species,including singlet oxygen,might play an important role in its phototoxicity.In this work,we studied effects of cholesterol and saturation of fatty acid phospholipids on peroxidation of liposomal lipids induced by UVA irradiation in the presence of chlorpromazine by measuring lipid hydroperoxides using HPLC-EC(Hg)and the iodometric assay.Our study shows that the CPZ-photosensitized peroxidation of lipids is modified by cholesterol and the type of phospholipids present in the liposomes.Thus in liposomes made of the unsaturated l-palmitoyl-2-oleoyl-phosphatidylcholine(POPC),chlorpromazine photosensitized strong peroxidation of lipids,which was mainly due to generation of singlet oxygen.In such liposomes,CPZ-photosensitized peroxidation of lipids was decreased,in a dose-dependent manner,by addition of cholesterol.On the other hand,in liposomes made of dimyristoyl-phosphatidylcholine(DMPC)and cholesterol peroxidation of lipids was 5 fold slower,while generation of singlet oxygen was reduced over 20 fold.Importantly,cholesterol had no effect on lipid peroxidation in POPC and DMPC liposomes induced by other photosensitizers such as Rose Bengal and merocyanine 540.We postulate that the effect of cholesterol on peroxidation of lipids in liposomal membranes,photosensitized by chlorpromazine,is mostly due to the cholesterol-dependent modulation of CPZ partition in such membranes,which dramatically lowers the efficiency of the photoexcited CPZ to generate singlet oxygen.