DNA photosensitization by indoprofen – is DNA damage photoinduced by indoprofen or by its photoproducts?

Abstract

The in vitro photosensitizing activity of indoprofen, a non-steroidal anti-inflammatory drug, toward DNA has been studied by gel sequencing experiments using ³²P-end labelled synthetic oligonucleotides in phosphate buffered solution. Upon irradiation at λ > 320 nm, piperidine-sensitive lesions were induced in single- and double-stranded DNA, exclusively at the position of guanine bases. In single-stranded DNA, all G sites were modified. This pattern of photooxidative damage without isotopic effect in deuterium oxide, is characteristic of a Type I mechanism involving electron transfer from the base to the excited drug. In duplex DNA, a Type I process was also observed since selective DNA breakage occurred with high selectivity at 5′-G of a 5′-GG-3′sequence. When the oligonucleotide displays TT sites, an energy transfer process becomes predominant, giving rise to the formation of thymine dimers as evidenced by using T4 endonuclease V. Moreover, the methyl ester of indoprofen has been synthesized in order to study the influence of the indoprofen photochemical properties in DNA photosensitization. The poor efficiency of this compound shows that the drug itself is not directly implicated in DNA photodamage and seems to imply the involvement of indoprofen photoproducts.