Lipid peroxidative potency of photosensitized thiazide diuretics

We examined the lipid peroxidative potency and photohemolytic activity of thiazide diuretics, especially penflutizide (PFZ), to determine the molecular mechanism of thiazide phototoxicity. Ultraviolet A irradiation of squalene in the presence of PFZ, hydrochlorothiazide, methiclothiazide, benzylhydrochlorothiazide, or trichlormethiazide induced in vitro peroxidation as measured by production of the hydroperoxides and thiobarbituric acid-reactive substances. Among the thiazides, PFZ showed the highest potency to photooxidize lipids. PFZ-photosensitized peroxidation of squalene was repressed by the presence of sodium azide or 2,5-dimethylfuran and was accelerated in a D2O suspension. These findings suggest the participation of singlet oxygen in PFZ photoperoxidation of squalene (type II mechanism). PFZ-photosensitized lysis of red blood cells (RBC) accompanied by formation of hydroperoxides in RBC membrane lipids was also noted. These results suggest that membrane lipids can be one of the target molecules of thiazide phototoxicity.