Drug Safety Research Laboratories, Astellas Pharma Inc, 1-6 Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan.
J Proteome Res. 2013 Mar 1;12(3):1399-407. doi: 10.1021/pr3010452. Epub 2013 Feb 6.
Nonsteroid anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs currently available. The most frequently reported serious side effects associated with NSAIDs are gastric mucosal ulceration and gastric hemorrhage. Presently, these side effects are only detectable by endoscopy, however, and no biomarkers have yet been identified. The ability to identify serum biomarkers would likely improve the safety of NSAID use. In this study we performed capillary electrophoresis-mass spectrometry (CE-MS)-based metabolomic profiling in stomach extract and serum from rats administered NSAIDs. Results showed drug-induced decreases in levels of citrate, cis-aconitate, succinate, 3-hydroxy butanoic acid, o-acetyl carnitine, proline, and hydroxyproline. We consider that these changes are due to NSAID-induced depression of mitochondrial function and activation of collagenase by lesions in the stomach. In addition, four of these changes in metabolite levels in the stomach were significantly correlated with changes in the serum. While further study is needed to clarify the mechanism of change in the level of these biomarkers, limitation of indications, and extrapolation to humans, these new serum biomarker candidates of gastric injury may be useful in the monitoring of NSAID-induced tissue damage.
非甾体抗炎药（NSAIDs）是目前应用最广泛的处方药物之一。与 NSAIDs 相关的最常见的严重副作用是胃黏膜溃疡和胃出血。目前，这些副作用只能通过内窥镜检测到，但是还没有发现生物标志物。如果能够识别血清生物标志物，可能会提高 NSAID 使用的安全性。在这项研究中，我们对给予 NSAIDs 的大鼠的胃提取物和血清进行了基于毛细管电泳-质谱（CE-MS）的代谢组学分析。结果表明，药物诱导的柠檬酸、顺乌头酸、琥珀酸、3-羟基丁酸、o-乙酰肉碱、脯氨酸和羟脯氨酸水平降低。我们认为这些变化是由于 NSAID 诱导的线粒体功能抑制以及胃损伤导致的胶原酶激活所致。此外，胃中这四种代谢物水平的变化与血清中的变化显著相关。虽然需要进一步研究来阐明这些生物标志物水平变化的机制、适应证的限制以及向人类的推断，但是这些新的胃损伤血清生物标志物候选物可能有助于监测 NSAID 诱导的组织损伤。
