Pefloxacin-induced achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen.
Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.
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
D000111:Acetylcysteine / Q000494:pharmacology; D000125:Achilles Tendon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D015366:Pefloxacin / Q000633:toxicity*; D011509:Proteoglycans / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D013462:Sulfur Radioisotopes
D000890:Anti-Infective Agents; D000975:Antioxidants; D011509:Proteoglycans; D013462:Sulfur Radioisotopes; D015366:Pefloxacin; D003094:Collagen; D000111:Acetylcysteine