Tomisato Wataru, Tsutsumi Shinji, Hoshino Tatsuya, Hwang Hyun-Jung, Mio Mitsunobu, Tsuchiya Tomofusa, Mizushima Tohru
Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Biochem Pharmacol. 2004 Feb 1;67(3):575-85. doi: 10.1016/j.bcp.2003.09.020.
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.
使用非甾体抗炎药（NSAIDs）时遇到的一个主要临床问题是胃肠道并发症。我们之前报道过NSAIDs在体外可诱导坏死和凋亡。我们在此研究了NSAIDs这种细胞毒性作用的环氧化酶（COX）依赖性及其与NSAIDs诱导的胃部病变的关系。除罗非昔布外，所有选择性COX-2抑制剂均能观察到NSAIDs诱导的坏死和凋亡，且外源性添加前列腺素E2不能抑制这种作用，这表明NSAIDs的细胞毒性似乎与COX的抑制作用无关。静脉注射吲哚美辛可完全抑制胃黏膜中的COX活性，但未产生胃部病变。口服选择性COX-2抑制剂，在胃黏膜中不抑制COX活性，也未产生胃部病变。有趣的是，除罗非昔布外的所有选择性COX-2抑制剂与静脉注射吲哚美辛联合口服时，明显产生了胃部病变。这些结果表明，除了NSAIDs对COX的抑制作用外，NSAIDs的直接细胞毒性可能也参与了NSAIDs诱导的胃部病变。
