ABSTRACT
The photodegradation products of hydrochlorothiazide produced by ultraviolet (UV) radiation were investigated for their phototoxicity utilizing the photohemolysis and Candida albicans tests. Hydrochlorothiazide was irradiated for 30, 60, 90 and 120 min with a 250 W xenon arc lamp using a WG295 cut-off filter. Irradiation of hydrochlorothiazide resulted in the gradual decrease of all three absorption bands (225, 270 and 320 nm), the blue shift of the 225 nm band, and the appearance of a new band around 290 nm. Since previous results demonstrated that photosubstitution of chloride could occur, the main product of this photolysis most likely is ethoxyhydrochlorothiazide. The photohemolysis test revealed a significant increase in photohemolysis observed in the photodegradation products produced after 60, 90 and 120 min of UV irradiation. This increase in hemolysis value directly correlated with the UV-irradiation time. However, there was no significant phototoxic killing of yeast in the Candida albicans test. This suggests photodegradation products of hydrochlorothiazide may play an important role in phototoxicity by acting on the cell membrane, but not on DNA. Considering the high in vitro phototoxicity observed in bendroflumethiazide and the data presented here, substitution of chloride seems to be responsible for the increased phototoxicity of hydrochlorothiazide.
Subject(s)
Antihypertensive Agents/radiation effects , Dermatitis, Phototoxic/etiology , Hydrochlorothiazide/radiation effects , Sodium Chloride Symporter Inhibitors/radiation effects , Ultraviolet Rays , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Candida albicans/drug effects , Diuretics , Erythrocytes/drug effects , Hemolysis/drug effects , Hemolysis/radiation effects , Humans , Hydrochlorothiazide/chemistry , Hydrochlorothiazide/pharmacology , Photolysis , Sodium Chloride Symporter Inhibitors/chemistry , Sodium Chloride Symporter Inhibitors/pharmacologyABSTRACT
The diuretics acetazolamide, bemetizide, bendroflumethiazide, benzthiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlorazanile, chlorothiazide, chlortalidone, clopamide, cyclopenthiazide, cyclothiazide, diazoxide, etozoline, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, mefruside, metolazone, piretanide, polythiazide, trichlormethiazide, and xipamide were screened in vitro for phototoxic effects by means of a photohemolysis test. In all, 19 out of the 25 test substances revealed phototoxic hemolytic properties after irradiation with either solar stimulating irradiation, UVA and/or visible light. Addition of the antioxidants ascorbic acid, alpha-tocopherole or superoxide dismutase significantly inhibited the phototoxic hemolysis, as well as did investigations carried out in a nitrogen rich atmosphere, findings which indicate the involvement of reactive oxygen species in the phototoxic process.
Subject(s)
Antioxidants/pharmacology , Benzothiadiazines , Erythrocytes/drug effects , Hemolysis/radiation effects , Nitrogen/pharmacology , Sodium Chloride Symporter Inhibitors/antagonists & inhibitors , Diuretics , Erythrocytes/physiology , Erythrocytes/radiation effects , Hemolysis/drug effects , Humans , Sodium Chloride Symporter Inhibitors/pharmacology , Sodium Chloride Symporter Inhibitors/radiation effects , Superoxide Dismutase/pharmacology , Ultraviolet Rays , Vitamin E/pharmacologyABSTRACT
Ethanolic solutions of three thiazide diuretics, chlorothiazide, hydrochlorothiazide and trichlormethiazide, were irradiated with a high-pressure mercury lamp. The products were isolated and their first-derivative UV spectra in ethanol were recorded and compared to those of the parent compounds. The determination of the parent compounds in the presence of the decomposition products was carried out at wavelengths near 220 nm using the zero-crossing technique. Three reversed-phase HPLC methods were also developed for the analysis of the parent compounds. In parallel analyses of the reaction mixtures a good correlation was achieved between these two methods in the determination of hydrochlorothiazide and trichlormethiazide while there was greater variation in the results of chlorothiazide.
Subject(s)
Sodium Chloride Symporter Inhibitors/analysis , Chlorothiazide/analysis , Chlorothiazide/chemistry , Chromatography, High Pressure Liquid , Diuretics , Hydrochlorothiazide/analysis , Hydrochlorothiazide/chemistry , Light , Photolysis , Sodium Chloride Symporter Inhibitors/chemistry , Sodium Chloride Symporter Inhibitors/radiation effects , Spectrophotometry, Ultraviolet , Trichlormethiazide/analysis , Trichlormethiazide/chemistryABSTRACT
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.
Subject(s)
Lipid Peroxides/metabolism , Sodium Chloride Symporter Inhibitors/radiation effects , Benzothiadiazines/radiation effects , Deuterium , Diuretics , Dose-Response Relationship, Radiation , Erythrocytes , Hemolysis , In Vitro Techniques , Oxidation-Reduction , Photochemistry , Photosensitivity Disorders , Squalene , Ultraviolet RaysABSTRACT
Photoinduced genotoxicity of benzothiadiazine diuretics was studied with regard to mutagenic and lambda prophage-inducing activities in E. coli. Irradiation of E. coli with near-ultraviolet light in the presence of hydrochlorothiazide or methyclothiazide caused mutations of strain Hs30R argF(Am) to the prototrophic phenotype and induction of lambda from the lysogenic bacteria AB1157(lambda). Both drugs showed nearly the same amount of activity. Penfluzide showed much less mutagenic and much less prophage-inducing activity than did hydrochlorothiazide and methyclothiazide.
Subject(s)
Escherichia coli/drug effects , Sodium Chloride Symporter Inhibitors/pharmacology , Virus Activation/drug effects , Bacteriophage lambda/drug effects , Bacteriophage lambda/growth & development , Benzothiadiazines/pharmacology , Benzothiadiazines/radiation effects , Diuretics , Hydrochlorothiazide/pharmacology , Hydrochlorothiazide/radiation effects , Methyclothiazide/pharmacology , Methyclothiazide/radiation effects , Mutagenicity Tests , Sodium Chloride Symporter Inhibitors/radiation effects , Ultraviolet RaysABSTRACT
UV irradiation (365 nm) of air-saturated methanol solutions of 20 drugs absorbing in the 300--400 nm region gave rise to oxygen uptake, as determined with a polarographic oxygen electrode. The drugs were tested for photosensitizing capability by either a Type I (free radical) or a Type II (single molecular oxygen) mechanism. This testing was done by the inclusion of either acrylamide or 2,5-dimethylfuran in the irradiated drug solution, with observation of the subsequent polymerization or oxidation, respectively. Phenothiazine and thiazide derivatives appear capable of photosensitization by both mechanisms; promethazine, trifluoperazine, and furosemide show relatively high reactivity. Diazepam (weak), hexachlorophene, aminacrine, pyrilamine, tetracycline, demeclocycline, quinine, and anthracene (strong) react only by a Type II mechanism, with a photosensitizing efficiency increasing in the order given. A correlation appears to exist with reports of in vivo photosensitivity.