Mechanism of DNA cleavage mediated by photoexcited non-steroidal antiinflammatory drugs.
DNA damage photoinduced by four nonsteroidal antiinflammatory drugs (NSAID) have been investigated by neutral agarose gel electrophoresis. Upon irradiation at 300 nm, in phosphate buffered solution, benoxaprofen, naproxen, ketoprofen, tiaprofenic acid photosensitized the formation of single-strand breaks (SSB) in double stranded supercoiled phi X174 DNA. The efficiency of the cleavage is higher in argon saturated solutions than in aerated solutions and it is not correlated with the quantum yield of photodegradation of the drugs. Simultaneously with the DNA strand breaks, NSAID promote a weak reduction of the electrophoretic mobility of the supercoiled form that may be attributed to the formation of pyrimidine dimers or other DNA unwinding products. These photodimerization processes suggest the involvement of a triplet-triplet energy transfer between NSAID and DNA. Addition of mannitol and superoxide dismutase decreases the efficiency of the cleavage suggesting that HO. and O2.- are involved in the DNA cleavage. Unexpectedly, addition of sodium azide quenches the cleavage both in aerated or in deaerated solutions. Substituting H2O by D2O does not change the number of SSB thus suggesting that 1O2 does not take an important place in the cleavage of DNA. From our data we tentatively assume that the cleavage occurs through a radical mechanism that may involve in a first step an energy or an electron transfer. Gel sequencing on NSAID-photoinduced DNA breakage exhibits no particular specificity except in the case of benoxaprofen where a slight selectivity for cytosine is observed.
Artuso
T
T
Laboratoire des IMRCP, URA 470 du CNRS, Université Paul Sabatier, Toulouse, France.
Bernadou
J
J
Meunier
B
B
Piette
J
J
Paillous
N
N
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000528:radiation effects*; D010584:Bacteriophage phi X 174; D001483:Base Sequence; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000528:radiation effects; D004279:DNA, Viral / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D008969:Molecular Sequence Data; D014466:Ultraviolet Rays
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004277:DNA, Single-Stranded; D004279:DNA, Viral