title: The in vivo rat skin photomicronucleus assay: phototoxicity and photogenotoxicity evaluation of six fluoroquinolones.
abstract: An in vivo photomicronucleus test (MNT) using rat skin, the target organ for photoirritancy and carcinogenicity, was recently described. The assay was evaluated using fluoroquinolone (FQ) antibiotics with varying degrees of phototoxic potency (i.e. sparflocacin [SPFX], lomefloxacin [LOFX], ciprofloxacin [CIFX], levofloxacin [LEFX], gemifloxacin [GEFX] and gatifloxacin [GAFX]) using a solar simulator producing both UVA and UVB (ratio 23:1). Experiments were performed at The Netherlands Organisation for Applied Scientific Research (TNO) and GlaxoSmithKline (GSK) to investigate interlaboratory variability, including evaluation of phototoxicity (clinical signs), micronucleus induction and histopathology. The potency of micronuclei (MN) formation in rat skin induced by the FQs was SPFX = LOFX > CIFX = LEFX, however, MN induction was only statistically significant for SPFX and LOFX. In both laboratories, GEFX and GAFX did not increase the MN frequencies compared to the irradiated vehicle control. Signs of phototoxicity, including clinical and histopathological changes, were observed with SPFX and LOFX to a similar degree as the positive control, 8-methoxypsoralen. In addition, there were some clinical signs of phototoxicity seen with CIFX, LEFX, GEFX and GAFX, but not always in both laboratories for CIFX, GEFX and GAFX and when observed, these were considered only mild. Of these, only LEFX also showed histopathological changes. In all studies, photogenotoxic potency correlated with photocarcinogenic potential and moreover, photogenotoxicity was not observed in the absence of phototoxicity. The results of the TNO/GSK study indicate that the in vivo rat skin photoMNT may be a promising tool for detection of photoclastogencity and photoirritancy in the skin/eye in the same animal. Given the association between the MNT and cancer, the skin photoMNT may also provide a promising tool for the early detection of photocarcinogenesis and help bridge the gap in the existing photosafety testing paradigm.
authors.affiliation: TNO Triskelion, Utrechtseweg 48, 3704 HE Zeist, The Netherlands.
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Reus
authors.forename: Mustafa
authors.initials: M
authors.lastname: Usta
authors.forename: Julia D
authors.initials: JD
authors.lastname: Kenny
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Clements
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pruimboom-Brees
authors.forename: Mike
authors.initials: M
authors.lastname: Aylott
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Lynch
authors.forename: Cyrille A M
authors.initials: CA
authors.lastname: Krul
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D020552:Comet Assay / Q000379:methods; D017484:Dermatitis, Phototoxic / Q000473:pathology*; D024841:Fluoroquinolones / Q000633:toxicity*; D008297:Male; D015162:Micronucleus Tests / Q000379:methods*; D009426:Netherlands; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones