Proteoglycan and collagen biochemical variations during fluoroquinolone-induced chondrotoxicity in mice.
Although fluoroquinolone antibacterials have a broad therapeutic use, with a relatively low incidence of severe side effects, they have been reported to induce lesions in the cartilage of growing animals by a mechanism that remains unclear. This study was undertaken to determine the potentially deleterious effect of a high dose of pefloxacin (400 mg/kg of body weight) on two main constituents of cartilage in mice, i.e., proteoglycans and collagen. Variations in levels of proteoglycan anabolism measured by in vivo [(35)S]sulfate incorporation into cartilage and oxidative modifications of collagen assessed by detection of carbonyl derivatives were monitored after administration of pefloxacin. Treatment of mice with 1 day of pefloxacin treatment significantly decreased the rate of biosynthesis of proteoglycan for the first 24 h. However, no difference was observed after 48 h. The decrease in proteoglycan synthesis was accompanied by a marked drop in serum sulfate concentration and a concomitant increase in urinary sulfate excretion. The decrease in proteoglycan synthesis, also observed ex vivo, may suggest a direct effect of pefloxacin on this process, rather than it being a consequence of a low concentration of sulfate. On the other hand, treatment with pefloxacin for 10 days induced oxidative damage to collagen. In conclusion, this study demonstrates, for the first time, that pefloxacin administration to mice leads to modifications in the metabolism and integrity of extracellular proteins, such as collagen and proteoglycans, which may account for the side effects observed. These results offer new insights to explain quinolone-induced disorders in growing articular cartilage.
Simonin
M A
MA
Department of Pharmacology, UMR 7561 CNRS-Université Henri Poincaré-Nancy I "Physiopathologie et Pharmacologie Articulaires," Faculté de Médecine, Vandoeuvre-lès-Nancy, France.
Gegout-Pottie
P
P
Minn
A
A
Gillet
P
P
Netter
P
P
Terlain
B
B
D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001168:Arthritis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D015366:Pefloxacin / Q000008:administration & dosage / Q000494:pharmacology; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000502:physiology; D013431:Sulfates / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013997:Time Factors
D000890:Anti-Infective Agents; D011509:Proteoglycans; D017382:Reactive Oxygen Species; D013431:Sulfates; D013462:Sulfur Radioisotopes; D015366:Pefloxacin; D003094:Collagen