Title
The in vivo rat skin photomicronucleus assay: Phototoxicity and photogenotoxicity evaluation of six fluoroquinolones
Author
Reus, A.A.
Usta, M.
Kenny, J.D.
Clements, P.J.
Pruimboom-Brees, I.
Aylott, M.
Lynch, A.M.
Krul, C.A.M.
Publication year
2012
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. © The Author 2012. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.
Subject
Triskelion BV
TARA - Toxicology and Risk Assessment
TNO Bedrijven
Biomedical Innovation
Research
Healthy Living
ciprofloxacin
gatifloxacin
gemifloxacin
levofloxacin
lomefloxacin
methoxsalen
quinoline derived antiinfective agent
sparfloxacin
animal tissue
article
carcinogenicity
controlled study
epidermis cell
female
genotoxicity
hairless mouse
histopathology
in vitro study
in vivo study
micronucleus
micronucleus test
nonhuman
phototoxicity
priority journal
rat
single drug dose
skin
Sprague Dawley rat
To reference this document use:
http://resolver.tudelft.nl/uuid:89d58ebb-a2a7-4a1c-a0d6-8e7363828b00
DOI
https://doi.org/10.1093/mutage/ges038
TNO identifier
466454
ISSN
0267-8357
Source
Mutagenesis, 27 (6), 721-729
Bibliographical note
Chemicals/CAS: ciprofloxacin, 85721-33-1; gatifloxacin, 112811-59-3, 180200-66-2; gemifloxacin, 175463-14-6, 204519-65-3, 210353-53-0, 210353-55-2, 210353-56-3; levofloxacin, 100986-85-4, 138199-71-0; lomefloxacin, 98079-51-7; methoxsalen, 298-81-7, 8004-26-0; sparfloxacin, 111542-93-9
Document type
article