Comparison of DNA damage photoinduced by ketoprofen, fenofibric acid and benzophenone via electron and energy transfer.

Ketoprofen (KP) and fenofibrate, respectively, anti-inflammatory and hypolipidemiant agents, promote anormal photosensitivity in patients and may induce photoallergic cross-reactions correlated to their benzophenone-like structure. Here, their ability to photosensitize the degradation of biological targets was particularly investigated in DNA. The photosensitization of DNA damage by KP and fenofibric acid (FB), the main metabolite of fenofibrate, and their parent compound, benzophenone (BZ), was examined on a 32P-end-labeled synthetic oligonucleotide in phosphate-buffered solution using gel sequencing experiments. Upon irradiation at lambda > 320 nm, piperidine-sensitive lesions were induced in single-stranded oligonucleotides by KP, FB and BZ at all G sites to the same extent. This pattern of damage, enhanced in D2O is characteristic of a Type-II mechanism. Spin trapping experiments using 2,2,6,6-tetramethyl-4-piperidone have confirmed the production of singlet oxygen during drug photolysis. On double-stranded oligonucleotides, highly specific DNA break occurred selectively at 5'-G of a 5'-GG-3' sequence, after alkali treatment. Prolonged irradiation led to the degradation of all G residues, with efficiency decreasing in the order 5'-GG > 5'-GA > 5'-GC > 5'-GT, in good agreement with the calculated lowest ionization potentials of stacked nucleobase models supporting the assumption of a Type-I mechanism involving electron transfer, also observed to a lesser extent with adenine. Cytosine sites were also affected but the action of mannitol which selectively inhibited cytosine lesions suggests, in this case, the involvement of hydroxyl radical, also detected by electronic paramagnetic resonance using 5,5-dimethyl-1-pyrrolidine-1-oxide as spin trap. On a double-stranded 32P-end-labeled 25-mer oligonucleotide containing TT and TTT sequences, the three compounds were found to photosensitize by triplet-triplet energy transfer the formation of cyclobutane thymine dimers detected using T4 endonuclease V.

Photosensitivity to ketoprofen: mechanisms and pharmacoepidemiological data.

The topical use of nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for moderate acute and chronic painful conditions, is one of several strategies used to improve the tolerability profile of NSAIDs, particularly with regard to gastric and renal adverse effects. However, topical NSAIDs can induce photosensitivity. Among the different NSAIDs used topically, ketoprofen has often been implicated in photosensitivity reactions. Photosensitivity includes both phototoxic and photoallergic reactions. Phototoxicity can be studied in the cell system and on biological targets such as cellular membranes or DNA. In hepatocyte cultures, data suggest that radical intermediates play a role in ketoprofen-photosensitised damage by cell membrane lysis. Photosensitised lysis of red blood cells has been employed as an indicator of membrane damage. Ketoprofen irradiation promotes the photolysis of erythrocyte suspensions. The drug is able to induce photoperoxidation of linoleic acid in the photo-induced lipid peroxidation process. The results obtained from the addition of radical scavengers suggest the involvement of free radicals in these processes. Ketoprofen may induce DNA damage in vitro upon irradiation. DNA, in the presence of ketoprofen, undergoes single strand breaks involving hydroxyl radicals as evidenced by the use of scavengers. Simultaneously with single strand breaks, pyrimidine dimers are formed by an energy transfer mechanism. The oxygen-dependence of both processes suggest competition between a radical process leading to DNA cleavage and a poorly efficient energy transfer between ketoprofen and pyrimidines at the origin of the dimerisation process. Photoallergy is due to a cell-mediated hypersensitivity response involving immunological reactions. Therefore, it only occurs in previously sensitised individuals and requires a latency period of sensitisation. Among NSAIDs, ketoprofen is the main drug involved in this photoallergic contact dermatitis. Cross-sensitivity reactions with other arylpropionic acid derivatives, such tiaprofenic acid, fenofibrate or oxybenzone-harbouring benzoyl ketone or benzophenone may also occur. Finally, the higher frequency of such adverse reactions with ketoprofen could be accounted for by its chemical structure and the variety of chemical reactions that give rise to phototoxic effects. The widespread and repeated use of these agents may lead to sensitisation, incurring a greater risk of systemic allergic reactions with oral NSAIDs or other drugs recognised to induce cross-reactions. Physicians and pharmacists should advise patients and inform them of the risks of topical NSAIDs which are often dispensed as over the counter drugs.