NONSTEROIDAL ANTIINFLAMMATORY DRUG-PHOTOSENSITIZED FORMATION OF PYRIMIDINE DIMER IN DNA

Phototoxic nonsteroidal antiinflammatory drugs (NSAIDs) may induce DNA damage in vitro upon irradiation. In this study, we investigated the ability of ketoprofen (KP), tiaprofenic acid (Tia), naproxen (NP) and indomethacin (IND) to photosensitize the formation of pyrimidine dimer s and single strand breaks. Both kinds of damage were sought by analyz ing DNA-drug mixtures irradiated at 313 nm by agarose gel electrophore sis. The formation of pyrimidine dimers was evidenced by using endonuc lease V from bacteriophage T4 and compared to that induced by acetophe none, a well-known photosensitizer of thymine dimerization. Upon irrad iation of DNA alone, pyrimidine dimers were observed while single stra nd breaks were not detected under our conditions. DNA, in the presence of NSAIDs, undergoes single strand breaks, the quantum yield of the D NA cleavage so induced (Phi C) varying from 5 x 10(-4) for KP to 10(-5 ) for IND. The formation of dimers was only increased in the presence of KP or Tia. The quantum yields of pyrimidine dimers formed by photos ensitization (Phi D) were 2 x 10(-4) for KP and 10(-5) for Tia, respec tively. The oxygen and concentration dependence of both processes was analyzed in the case of KP. In aerated solution, KP photoinduced cleav age of DNA was predominant on the photodimerization process of pyrimid ines, whereas in deaerated solution the cleavage was decreased End the dimerization increased. These results reflect competition between a r adical process leading to DNA cleavage and a poorly efficient energy t ransfer between the drug and the pyrimidines at the origin of the dime rization process. (C) 1998 Elsevier Science Inc.