Effects of food intake and oxidative stress on intestinal lesions caused by meloxicam and piroxicam in rats.
Large intestinal ulcers, bleeding and perforation are occasionally due to non-steroidal anti-inflammatory drugs (NSAID). In addition to suppression of prostaglandins synthesis, a number of factors have been implicated, including enterohepatic recirculation, food intake and vascular injury with oxygen free-radical generation. The present study aimed to determine the effect of food intake and the role of oxidative stress in the pathogenesis of intestinal injury induced by oral administration of meloxicam (preferential cyclooxygenase-2 inhibitor) vs. piroxicam (preferential cyclooxygenase-1 inhibitor). Therefore, the activity of oxidative stress-related enzymes such as myeloperoxidase, xanthine oxidase and superoxide dismutase, as well as levels of lipid peroxides and glutathione homeostasis were studied in an experimental model using re-fed rats. The animals treated with piroxicam (10-20 mg/kg) had a dose-dependent increase in the severity of intestinal lesions, but only the highest dose of meloxicam (15 mg/kg) caused macroscopic damage. The severity of piroxicam and meloxicam-induced damage was correlated with a significant increase of xantine oxidase activity and a decrease of superoxide dismutase activity and glutathione levels (P<0.05 and P<0.001 vs. control). In contrast, there was no significant neutrophil infiltration of the intestine after dosing. Our results support the hypothesis that oxygen free radicals, probably derived via the action of xantine oxidase, the decrease in superoxide dismutase activity, and depletion of mucosal glutathione contribute to the pathogenesis of meloxicam and piroxicam-induced intestinal ulceration in re-fed rats.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Profesor García González Street, 41012, Seville, Spain.
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Villegas
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Alarcón de la Lastra
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La Casa
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Motilva
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Martín
D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D005260:Female; D018565:Food-Drug Interactions; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism; D005980:Glutathione Reductase; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D000077239:Meloxicam; D008565:Membrane Proteins; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010894:Piroxicam / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase; D014456:Ulcer / Q000139:chemically induced*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D005979:Glutathione Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; C424443:Txnrd3 protein, mouse; D005978:Glutathione; D000077239:Meloxicam