Effects of oxicam inhibitors of cyclooxygenase on oxidative stress generation in rat gastric mucosa. A comparative study.
The aim of this study was to compare the effects of two nonsteroidal anti-inflammatory drugs (NSAID), members of the same family with a different cyclooxygenase (COX) inhibition selectivity, meloxicam, preferent COX-2 inhibitor, and piroxicam, preferent COX-1 inhibitor, on oxygen radical generation in rat gastric mucosa. Therefore, the activity of oxidative stress-related enzymes such as xanthine oxidase (XO), superoxide dismutase (SOD) and glutathione (GSH) homeostasis were studied in rats. Gastric prostaglandins (PG) were also assessed as a measure of COX-1 inhibition. Both oxicams produced a similar extent of the gastric mucosal damage and a significant decrease in PGE2 synthesis, however only piroxicam induced an increase of both myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)-alpha content in the gastric mucosa, indicating that neutrophil-derived free radicals were involved in gastric injury. Furthermore, both compounds reduced SOD activity and increased XO activity in gastric mucosa. Our results also revealed modifications in GSH metabolism: although glutathione peroxidase (GSH-px) activity was unaffected by meloxicam or piroxicam administration, both glutathione reductase (GSSG-rd) activity and total GSH content were significantly decreased after dosing. These results suggest that under our experimental conditions, meloxicam, preferential COX-2 inhibitor causes rates of gastric lesion in rats comparable to those seen with the traditional NSAID piroxicam, preferential COX-1 inhibitor. In addition to suppression of systemic COX activity, oxygen radicals, probably derived via the XO, and neutrophils play an important role in the production of damage induced by both oxicams. Moreover, the decrease in SOD activity and changes in glutathione homeostasis in gastric mucosa may also contribute to pathogenesis of meloxicam- or piroxicam-induced gastropathy.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Professor García González Street, 41012 Seville, Spain.
I
I
Villegas
M J
MJ
Martín
C
C
La Casa
V
V
Motilva
C Alarcón
CA
De La Lastra
D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D000077239:Meloxicam; D008565:Membrane Proteins; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D010894:Piroxicam / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D005978:Glutathione; D015232:Dinoprostone; D000077239:Meloxicam