Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions.
A major clinical problem encountered with the use of non-steroidal anti-inflammatory drugs (NSAIDs), is gastrointestinal complications. We previously reported that NSAIDs induce both necrosis and apoptosis in vitro. We here examined the cyclooxygenase (COX) dependency of this cytotoxic effect of NSAIDs and its involvement in NSAID-induced gastric lesions. Necrosis and apoptosis by NSAIDs was observed with all selective COX-2 inhibitors except rofecoxib and was not inhibited by exogenously added prostaglandin E2, suggesting that cytotoxicity of NSAIDs seems to be independent of the inhibition of COX. Intravenously administered indomethacin, which completely inhibited COX activity at gastric mucosa, did not produce gastric lesions. Orally administered selective COX-2 inhibitors, which did not inhibit COX at gastric mucosa, also did not produce gastric lesions. Interestingly, a combination of the oral administration of each of all selective COX-2 inhibitors except rofecoxib with the intravenous administration of indomethacin clearly produced gastric lesions. These results suggest that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs may be involved in NSAID-induced gastric lesions.
Tomisato
Wataru
W
Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Tsutsumi
Shinji
S
Hoshino
Tatsuya
T
Hwang
Hyun-Jung
HJ
Mio
Mitsunobu
M
Tsuchiya
Tomofusa
T
Mizushima
Tohru
T
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D017209:Apoptosis; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D015232:Dinoprostone / Q000378:metabolism*; D004347:Drug Interactions; D006168:Guinea Pigs; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009336:Necrosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013272:Stomach Diseases / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone