Quinolone antibiotic photodynamic production of 8-oxo-7, 8-dihydro-2'-deoxyguanosine in cultured liver epithelial cells.
To study the basis for the phototoxicity of quinolones, a class of synthetic antibacterials, the photodynamic ability to mediate 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) formation in cultured cells was measured for lomefloxacin (LMX), which is strongly associated with clinical phototoxicity in humans, and ciprofloxacin (CFX), which has few reports of phototoxicity. Adult rat liver (ARL-18) cells were exposed to the quinolones in the presence of UVA and DNA was extracted and analyzed by HPLC with electrochemical detection. Low levels of 8-oxo-dG were found in the DNA of nonirradiated ARL-18 cells and this was increased up to 6-fold in the presence of either LMX (50-400 microM) or up to 3.6-fold in the presence of CFX (50-400 microM) and UVA (20 J/cm2) when compared to the UVA control. Comparing separate experiments with LMX and CFX, LMX produced greater levels of 8-oxo-dG either after dark exposure or after UVA exposure at 20 J/cm2. Also, LMX and CFX were both shown to photodegrade in the presence of UVA, and it was determined that UVA photoinstability alone does not reflect phototoxic potential. These data suggest that the photodynamic potential of LMX and CFX to produce 8-oxo-dG may relate to their human clinical phototoxicity profile. We suggest that the observed clinical phototoxicity is mediated through a UVA photodynamic effect on the quinolone to form reactive oxygen species in the presence of molecular oxygen. The findings indicate that 8-oxo-dG formation can serve as a marker for the potential phototoxicity of new quinolones.
Rosen
J E
JE
American Health Foundation, Valhalla, NY, USA.
Prahalad
A K
AK
Schlüter
G
G
Chen
D
D
Williams
G M
GM
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004563:Electrochemistry; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D024841:Fluoroquinolones; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017319:Photosensitizing Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D017319:Photosensitizing Agents; D015363:Quinolones; D002939:Ciprofloxacin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C053091:lomefloxacin