Differences in the photogenotoxic potential of two fluoroquinolones as shown in diploid yeast strain (Saccharomyces cerevisae) and supercoiled plasmid DNA.
Fluoroquinolones are antibiotics with a potential clinical side effect of phototoxicity and some are suspected to enhance UVA-induced tumorigenesis. The present study was designed to evaluate the recombinogenic and mutagenic potential of two highly photoreactive compounds, lomefloxacin and BAYy3118 when exposed to complete UVA (320-400 nm). In order to possibly increase the sensitivity of the test, we used a diploid mutant (D7-rad3) deficient in nucleotide excision repair and deriving from the tester strain D7 of the yeast Saccharomyces cerevisae. In agreement with previous reports, lomefloxacin had no effect in this system. Moreover, BAYy3118 was highly photocytotoxic and genotoxic especially when yeast cells were incubated in its presence in the dark before exposure to UVA radiation. Both fluoroquinolones were comparable in their ability to photo-induce DNA strand breaks or oxidative damage to purines and pyrimidines in supercoiled plasmid DNA, but agarose gel electrophoresis showed that BAYy3118 photoproducts could tightly interact with supercoiled plasmid DNA while lomefloxacin ones only induced strand breaks. These data suggest that phototoxicity of BAYy3118 was the result of a multistep mechanism: first, local photo oxidative stress is induced and secondly some of the photoproducts exerted genotoxic effects. This work also shows that very simple and complementary in vitro approaches can be very informative in the understanding of drug-induced phototoxicity.
Marrot
L
L
L'Oreal Advanced Research, Life Sciences Research, Investigative Toxicology Department, Aulnay Sous Bois, France. lmarrot@rechereche.loreal.com
Agapakis-Causse
C
C
D000251:Adenosine Triphosphatases / Q000235:genetics; D000890:Anti-Infective Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D004265:DNA Helicases / Q000235:genetics; D004278:DNA, Superhelical / Q000187:drug effects* / Q000528:radiation effects; D004171:Diploidy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D024841:Fluoroquinolones; D009152:Mutagenicity Tests; D009154:Mutation; D017319:Photosensitizing Agents / Q000633:toxicity*; D010957:Plasmids / Q000187:drug effects* / Q000528:radiation effects; D015363:Quinolones / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D014466:Ultraviolet Rays
D000890:Anti-Infective Agents; D004278:DNA, Superhelical; D024841:Fluoroquinolones; D017319:Photosensitizing Agents; D015363:Quinolones; D029701:Saccharomyces cerevisiae Proteins; C079807:Bay Y3118; D000251:Adenosine Triphosphatases; C061897:Rad3 protein, S cerevisiae; D004265:DNA Helicases; C053091:lomefloxacin