Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin cells: from DNA damage to apoptosis.
Photo-unstable chemicals sometimes behave as phototoxins in skin, inducing untoward clinical side-effects when exposed to sunlight. Some drugs, such as psoralens or fluoroquinolones, can damage genomic DNA, thus increasing the risk of photocarcinogenesis. Here, lomefloxacin, an antibiotic from the fluoroquinolone family known to be involved in skin tumor development in photoexposed mice, was studied using normal human skin cells in culture: fibroblasts, keratinocytes, and Caucasian melanocytes. When treated cells were exposed to simulated solar ultraviolet A (320-400 nm), lomefloxacin induced damage such as strand breaks and pyrimidine dimers in genomic DNA. Lomefloxacin also triggered various stress responses: heme-oxygenase-1 expression in fibroblasts, changes in p53 status as shown by the accumulation of p53 and p21 proteins or the induction of MDM2 and GADD45 genes, and stimulation of melanogenesis by increasing the tyrosinase activity in melanocytes. Lomefloxacin could also lead to apoptosis in keratinocytes exposed to ultraviolet A: caspase-3 was activated and FAS-L gene was induced. Moreover, keratinocytes were shown to be the most sensitive cell type to lomefloxacin phototoxic effects, in spite of the well-established effectiveness of their antioxidant equipment. These data show that the phototoxicity of a given drug can be driven by different mechanisms and that its biologic impact varies according to cell type.
Marrot
Laurent
L
Genotoxicity Group, L'Oreal Research, 1 avenue Eugene Schueller, 93600 Aulnay-sous-bois, France. lmarrot@recherche.loreal.com
Belaïdi
Jean Phillipe
JP
Jones
Christophe
C
Perez
Phillipe
P
Riou
Lydia
L
Sarasin
Alain
A
Meunier
Jean Roch
JR
D000890:Anti-Infective Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D024841:Fluoroquinolones; D015870:Gene Expression / Q000528:radiation effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008565:Membrane Proteins; D017319:Photosensitizing Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D012867:Skin / Q000166:cytology*; D012880:Skin Pigmentation / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D008565:Membrane Proteins; D017319:Photosensitizing Agents; D015363:Quinolones; D016159:Tumor Suppressor Protein p53; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C053091:lomefloxacin