Role of direct cytotoxic effects of NSAIDS in the induction of gastric lesions
Role of direct cytotoxic effects of NSAIDS in the induction of gastric lesions
复制标题
DOI：
10.1016/j.bcp.2003.09.020
复制
发表时间：
2004-02-01
影响因子：
5.8
通讯作者：
Mizushima, T
中科院分区：
文献类型：
--
作者：
Tomisato, W;Tsutsumi, S;Mizushima, T
使用非甾体抗炎药（NSAID）遇到的主要临床问题是胃肠道并发症。我们以前报道过非甾体抗炎药在体外同时诱导坏死和凋亡。我们在这里研究了环氧化酶（考克斯）的依赖性，这种非甾体抗炎药的细胞毒性作用，其参与非甾体抗炎药诱导的胃病变。除罗非昔布外，所有选择性考克斯-2抑制剂均观察到NSAID引起的坏死和凋亡，并且不受外源性前列腺素E-2的抑制，表明NSAID的细胞毒性似乎与考克斯的抑制无关。吲哚美辛可完全抑制胃粘膜考克斯活性，但不引起胃损伤。口服选择性考克斯-2抑制剂，在胃粘膜不抑制考克斯，也不产生胃病变。有趣的是，除了罗非昔布之外的所有选择性考克斯-2抑制剂的口服给药与吲哚美辛的静脉给药的组合明显产生胃损伤。这些结果表明，除了考克斯抑制非甾体类抗炎药，非甾体类抗炎药的直接细胞毒性可能参与非甾体类抗炎药诱导的胃病变。(C)2003年爱思唯尔公司All rights reserved.
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 E-2, 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. (C) 2003 Elsevier Inc. All rights reserved.