Phototoxic Lesions Induced by Quinolone Antibacterial Agents in Auricular Skin and Retina of Albino Mice

Abstract

The phototoxic effects of quinolone antimicrobial agents on mouse auricular skin and retina were examined histologically. Sparfloxacin at 50 or 100 mg/kg, which alone causes no histologic change, was orally administered to albino Balb/c mice, which were irradiated with ultraviolet A for 4 hr immediately after administration. In the auricle, degeneration of basal epidermal cells was sporadically observed at 2 hr (during the irradiation). Foci of slight edema with degenerated fibroblasts were seen in the dermis at 4 hr. Edema and neutrophil infiltration in the dermis became severe up to 96 hr. Initial changes in the retina were observed at 2 hr. Vacuolation of the photoreceptor segments (particularly the inner segment) was occasionally associated with swelling of retinal pigment epithelial cells. The segments became disorganized with time, and the outer nuclear layer showed reduced cellularity. The segments and layer were partially thinned and lost 96 hr later. Enoxacin at 400 and 800 mg/kg induced similar lesions to those of sparfloxacin. Levofloxacin caused similar lesions in the auricle but no change in the retina. The combination of oral administration of quinolone and ultraviolet A irradiation, which never caused apparent morphological changes alone, was shown to be able to induce phototoxic lesions in albino mice. Therefore, this method is thought to be useful to examine morphological changes caused by quinolone phototoxicity.

Stimulation of Prostaglandin Production by Quinolone Phototoxicity in Balb/c 3T3 Mouse Fibroblast Cells in Vitro

“…In contrast, treatment with LVFX up to 100 /ZM and UVA had no effect on PG concentration in the 3T3 cell culture medium. This lesser effect of LVFX in contrast to that of SPFX appears to be consistent with our previous in vivo study, in which oral administration of 50 mg/kg SPFX or 800 mg/kg LVFX followed by UVA irradiation induced auricular inflammation, while that of 400 mg/kg LVFX with UVA did not (Shimoda et al, 1993). Quinolones substituted with a fluorine at the 8 position of the quinolone ring have been reported to possess stronger phototoxic potential than quinolones with other substituents at this position (Domagala, 1994).…”

“…On the basis of our having previously demonstrated that auricular skin inflammation was induced by quinolone phototoxicity in Balb/c mice (Shimoda et al, 1993), Balb/c 3T3 mouse fibroblast cells obtained from American Type Culture Collection and maintained in our laboratory were used in the present study. The cells were seeded in 12-well culture plates coated with collagen type I (Iwaki Glass, Japan) at a uniform density of 5 X 10 4 cells/ml in RPMI medium 1640 with phenol red, supplemented with 10% FBS, penicillin (100 /zg/ml), and streptomycin (100 units/ml), followed by incubation for 72 hr at 37°C in a humidified 5% CO 2 incubator to approximately 100% monolayer confluence.…”

“…In the present study, we investigated the role of fibroblasts, which constitute a major component of the skin dermis, in quinolone phototoxicity in vitro by examining the release of inflammatory mediators PGE2, a potentiator of vascular hyperpermeability, 6-keto-PGF,,,, a metabolite of the potentiator of vascular hyperpermeability PGI 2 , and LTB 4 , a chemoattractant of polymorphonuclear leukocytes, from Balb/c 3T3 mouse fibroblast cells after incubation with SPFX or LVFX under UVA irradiation because dermal edema and neutrophil infiltration were the main histological findings in the auricular inflammation in our previous in vivo study (Shimoda et al, 1993).…”

“…These results suggest that PGs released from dermal fibroblasts in the simultaneous presence of quinolone and UVA could contribute in part to the development of skin inflammation in vivo, c A number of quinolone antibacterial agents, including lomefloxacin (LFLX), sparfloxacin (SPFX), ofloxacin (OFLX), ciprofloxacin (CPFX), fleroxacin (FLRX), and pefloxacin (PFLX), have been reported to induce photosensitivity in humans at a very low incidence (Food and Drug Administration, 1993;Christ and Lehnert, 1990;Yamaguchi et al, 1994). We previously reported that ultraviolet-A (UVA) irradiation for 4 hr following single oral administration of SPFX at 50 or 100 mg/kg, enoxacin (ENX) at 400 or 800 mg/kg, or levofloxacin (LVFX) at 800 mg/kg induced auricular inflammation consisting of dermal edema and neutrophil infiltration, leading to increased thickness of the auricle in albino mice (Shimoda et al, 1993). Antioxidants such as catalase and dimethyl sulfoxide inhibited the auricular thickening induced by SPFX phototoxicity in the early stage, while anti-inflammatory drugs such as indomethacin, dexamethasone, and phenidone, which inhibit the production of arachidonic acid metabolites mediated by cyclooxygenase, inhibited this thickening in both the early and later stages.…”

Photosensitivity-Induced Retinal Atrophy in Albino Rat

“…In their recent article, Shimoda et al (5) reported the occurrence of retinal atrophy in albino mice induced by quinolone. They stated, &dquo;Few reports have dealt with morphologic changes induced by drug phototoxicity; in particular, we are aware of no studies concerning retinal changes&dquo; (p. 555).…”