Different mechanisms for the photoinduced production of oxidative DNA damage by fluoroquinolones differing in photostability

Several fluoroquinolone antibacterial agents exhibit an adverse phototoxic effect in humans and are photo-cocarcinogenic in mice. The UV-induced produ ction of reactive oxygen species plays a role in the toxicity and may be in volved in carcinogenicity. Four fluoroquinolones were examined for the abil ity to photochemically produce oxidative damage in naked DNA, The major str uctural difference in the fluoroquinolones that would have an effect on the ir photostability is the functionality at the 8-position. At this position, 1-cyclopropyl-7-(2,8-diazbicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid (BAY y3118) contains a chlorine atom, lome floxacin a fluorine atom, ciprofloxacin a proton, and moxifloxacin a methox y group. The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) i n calf thymus DNA was assessed by HPLC with electrochemical detection, and strand breaks were measured in pBR322 with agarose gel electrophoresis, The relative photolability of the fluoroquinolones correlated to the extent of production of 8-oxodGuo and strand breaks, with both WA and UVB irradiatio n, in the following order: BAY y3118 similar to lomefloxacin > ciprofloxaci n > moxifloxacin. Experiments were performed to determine whether the mecha nism of damage was due to a type I (radical) or type II (singlet oxygen) pa thway. Nitrogen depletion of oxygen resulted in a decrease in the extent of formation of 8-oxodGuo, suggesting that oxygen was involved. The use of se lective radical or singlet oxygen inhibitors was inconclusive with respect to which pathway was involved. The use of D2O as a solvent, which would ext end the lifetime of singlet oxygen, suggested that this species is involved in the formation of 8-oxodGuo by moxifloxacin and ciprofloxacin, but not b y lomefloxacin and BAY y3118. Similarly, it was found that singlet oxygen w as not involved in strand break formation. Thus, the evidence suggests that fluoroquinolones can photochemically produce DNA damage by both type I and type II mechanisms.