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Toxicol Sci ; 118(1): 236-50, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20668001

ABSTRACT

In this paper, we have investigated the mechanism of phototoxicity of fluvastatin, an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in human keratinocytes cell line NCTC-2544. Fluvastatin underwent rapid photodegradation upon Ultraviolet-A (UVA) irradiation in buffered aqueous solution as shown by the changes in absorption spectra. Interestingly, no isosbestic points were observed but only a fast appearance of a spectral change, indicative of the formation of a new chromophore. The isolation and characterization of the main photoproduct revealed the formation of a polycyclic compound with a benzocarbazole-like structure. This product was also evaluated for its phototoxic potential. Cell phototoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide test after 72 h from the irradiation in the presence of fluvastatin. The results showed a reduction of the cell viability in a concentration and UVA dose-dependent manner. Surprisingly, the photoproduct showed a dramatic decrease of the cell viability that occurred at concentrations of an order of magnitude lower than the parent compound. Flow cytometric analysis indicated that fluvastatin and its main photoproduct induced principally necrosis as revealed by the large appearance of propidium iodide-positive cells and confirmed also by the rapid drop in cellular adenosine triphosphate levels. Interestingly, a rapid increase of intracellular calcium followed by an extensive cell lipid membrane peroxidation and a significant oxidation of model proteins were induced by fluvastatin and its photoproduct, suggesting that these compounds exerted their toxic effect mainly in the cellular membranes. On the basis of our results, the phototoxicity of fluvastatin may be mediated by the formation of benzocarbazole-like photoproduct that acts as strong photosensitizer.


Subject(s)
Carbazoles/metabolism , Fatty Acids, Monounsaturated/toxicity , Hydroxymethylglutaryl-CoA Reductase Inhibitors/toxicity , Indoles/toxicity , Photochemical Processes , Photosensitizing Agents/metabolism , Apoptosis/drug effects , Calcium/metabolism , Carbazoles/analysis , Carbazoles/toxicity , Cell Line, Transformed , Cell Membrane/drug effects , Cell Membrane/metabolism , Cell Survival/drug effects , Cell Survival/radiation effects , Chromatography, High Pressure Liquid , Fatty Acids, Monounsaturated/metabolism , Fatty Acids, Monounsaturated/radiation effects , Fluvastatin , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/radiation effects , Indoles/metabolism , Indoles/radiation effects , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/pathology , Lipid Peroxidation/drug effects , Photosensitizing Agents/analysis , Ultraviolet Rays
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