Involvement of reactive oxygen species, protein kinase C, and tyrosine kinase in prostaglandin E2 production in Balb/c 3T3 mouse fibroblast cells by quinolone phototoxicity.
We examined the effect of an antioxidant and protein kinase inhibitors on prostaglandin E2 (PGE2) release from Balb/c 3T3 mouse fibroblast cells induced by quinolone phototoxicity. Simultaneous administration of sparfloxacin (SPFX) or lomefloxacin (LFLX) at 12.5 to 100 microM and ultraviolet-A (UVA) irradiation for 10 min markedly elevated PGE2 concentration in the incubation medium, whereas levofloxacin (LVFX) at concentrations up to 100 microM and UVA irradiation did not increase PGE2 concentration. Pretreatment with 100 microM pyrrolidine dithiocarbamate (PDTC), an antioxidant, or 1 microM calphostin C, a selective inhibitor of protein kinase C (PKC), completely inhibited the elevation of PGE2 in the 24-h incubation medium; pretreatment with 10 microM H7, a cyclic nucleotide-dependent protein kinase, and PKC or 1 microM herbimycin A, a tyrosine kinase inhibitor, inhibited the PGE2 elevation by 29 to 39%. Conversely, 25 nM staurosporine significantly augmented the PGE2 elevation by quinolones plus UVA. Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) were not detected in the incubation medium of 3T3 cells after quinolone plus UVA, corresponding to the lack of effect of antibodies against IL-1alpha, IL-1beta, and TNFalpha on PGE2 release from 3T3 cells. These results suggest that PGE2 production in 3T3 cells by quinolone phototoxicity is modulated by reactive oxygen species, PKC, and tyrosine kinase, but not by IL-1 or TNFalpha.
Shimoda
K
K
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Kato
M
M
D016475:3T3 Cells; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D002462:Cell Membrane / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis*; D024841:Fluoroquinolones; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D017319:Photosensitizing Agents / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015363:Quinolones / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014466:Ultraviolet Rays
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007375:Interleukin-1; D017319:Photosensitizing Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D015232:Dinoprostone; C053091:lomefloxacin; C061363:sparfloxacin