TNO Triskelion, Utrechtseweg 48, 3704 HE Zeist, The Netherlands.
Mutagenesis. 2012 Nov;27(6):721-9. doi: 10.1093/mutage/ges038. Epub 2012 Aug 30.
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.
最近描述了一种使用大鼠皮肤的体内光微核试验（MNT），大鼠皮肤是光刺激性和致癌性的靶器官。该测定法使用具有不同光毒性效力的氟喹诺酮（FQ）抗生素进行了评估（即斯巴氟沙星[SPFX]、洛美沙星[LOFX]、环丙沙星[CIFX]、左氧氟沙星[LEFX]、吉米沙星[GEFX]和加替沙星[GAFX]），使用产生 UVA 和 UVB 的太阳模拟器（比例为 23:1）。实验在荷兰应用科学研究组织（TNO）和葛兰素史克（GSK）进行，以研究实验室间的变异性，包括光毒性（临床体征）、微核诱导和组织病理学评估。在大鼠皮肤中由 FQ 诱导的微核形成的效力为 SPFX = LOFX > CIFX = LEFX，然而，仅 SPFX 和 LOFX 的 MN 诱导具有统计学意义。在两个实验室中，与辐照的载体对照相比，GEFX 和 GAFX 均未增加 MN 频率。与阳性对照 8-甲氧基补骨脂素相比，SPFX 和 LOFX 观察到类似程度的光毒性迹象，包括临床和组织病理学变化。此外，CIFX、LEFX、GEFX 和 GAFX 也观察到一些光毒性迹象，但并非总是在两个实验室中都观察到 CIFX、GEFX 和 GAFX，并且当观察到这些迹象时，仅认为是轻度的。其中，只有 LEFX 还显示出组织病理学变化。在所有研究中，光遗传毒性效力与光致癌潜力相关，而且，在没有光毒性的情况下没有观察到光遗传毒性。TNO/GSK 研究的结果表明，体内大鼠皮肤光 MNT 可能是一种有前途的工具，用于在同一动物中检测皮肤/眼睛的光细胞毒性和光刺激性。鉴于 MNT 与癌症之间的关联，皮肤光 MNT 也可能为早期检测光致癌作用提供有前途的工具，并有助于缩小现有光安全性测试范例中的差距。
