Damage to mitochondria of cultured human skin fibroblasts photosensitized by fluoroquinolones.
The phototoxic fluoroquinolones ofloxacin, lomefloxacin, norfloxacin, ciprofloxacin and BAYy 3118 have ionizable groups with pKa values close to neutrality. Different ionic species of these fluoroquinolones, therefore, partition in various compartments and organelles of living cells according to their ionic equilibria. While all these fluoroquinolones accumulate in lysosomes, they more or less stain the rest of the cytoplasm of living HS 68 fibroblasts. As a result, photosensitized damage to other cytoplasmic sites than lysosomes can also be expected. Using microfluorometry and rhodamine 123 (Rh 123) as a specific fluorescent probe which is released from mitochondria by light absorption, we show that under ultraviolet A (UVA) irradiation norfloxacin and ciprofloxacin readily damage mitochondrial membranes. as evidenced by the UVA dose-dependent strongly accelerated release of Rh 123 from mitochondria in cells treated with norfloxacin and ciprofloxacin. Damages are already noticeable at UVA doses as low as 2 J/cm2. By contrast, no such photoinduced damage can be observed with ofloxacin, lomefloxacin and BAYy 3118, the latter being the most phototoxic derivative towards HS 68 fibroblasts. The initial photodamage induced by norfloxacin and ciprofloxacin can then propagate after the irradiation as shown by the strongly increased rate of release of Rh 123 from mitochondria of cells that have been incubated with these two fluoroquinolones and left in the dark after a pre-irradiation with 18 J/cm2 of UVA. Interestingly, the same pre-irradiation after cells have been treated with BAYy 3118 and lomefloxacin induces similar post-irradiation effects, although they have no apparent immediate photosensitizing action on mitochondria.
Ouédraogo
G
G
Laboratoire de Photobiologie, Muséum National d'Histoire Natulrelle, Paris, France.
Morlière
P
P
Santus
R
R
Miranda
Castell
J V
JV
D000890:Anti-Infective Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D024841:Fluoroquinolones; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D009643:Norfloxacin / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D017319:Photosensitizing Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D012867:Skin / Q000166:cytology
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D017319:Photosensitizing Agents; D015363:Quinolones; C079807:Bay Y3118; D002939:Ciprofloxacin; D015242:Ofloxacin; C053091:lomefloxacin; D009643:Norfloxacin