Mechanisms of quinolone phototoxicity

We examined the mechanisms of quinolone phototoxicity in vivo and in vitro. Simultaneous p.o. administration of a quinolone and ultraviolet-A (UVA) irradiation for 4 h induced auricular skin inflammation in BALB/c mice, including edema and neutrophil infiltration in the dermis. Antioxidants inhibited the inflammation in the early stage and cyclooxygenase inhibitors did in both the early and later stages, whereas 5-lipoxygenase inhibitors or histamine antagonists had no effect. The phototoxic inflammation was also induced in mast cell-deficient WBB6F1-W/Wv mice. Corresponding to the in vivo results, incubation with a quinolone under UVA irradiation stimulated BALB/c 3T3 mouse fibroblast cells to release prostaglandin E2 (PGE2) and 6-keto-PGF1alpha, but not leukotriene B4. In contrast, UVA-pre-irradiated quinolones did not affect PG release from fibroblasts. The PGE2 release was inhibited by cyclooxygenase inhibitors, antioxidants, protein kinase C (PKC) inhibitors and a tyrosine kinase (TK) inhibitor, but not by antibodies against tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1). These results lead to a hypothesis that reactive oxygen species generated from quinolones under UVA irradiation trigger PG release from dermal fibroblasts via PKC and TK activation, resulting in skin inflammation and that 5-lipoxygenase products, histamine, TNF alpha or IL-1 is ruled out from the mechanism.