Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine.
Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine.
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DOI：
10.1016/j.bbalip.2012.04.002
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Krishnamoorti R
中科院分区：
文献类型：
--
作者：
Lichtenberger LM;Zhou Y;Jayaraman V;Doyen JR;O'Neil RG;Dial EJ;Volk DE;Gorenstein DG;Boggara MB;Krishnamoorti R
非甾体抗炎药(NSAIDs)是应用最广泛的药物之一，但其治疗作用和副作用，尤其是胃肠道(GI)溃疡/出血的机制尚不清楚。在这项研究中，我们使用了许多生化、结构、计算和生物系统，包括傅立叶变换红外光谱(FTIR)。核磁共振(NMR)和表面等离子体共振(SPR)光谱，以及使用特定荧光膜探针的细胞培养，证明非类固醇抗炎药与两性离子磷脂，特别是磷脂酰胆碱(PC)具有很强的亲和力，形成离子和疏水结合，这些磷脂在性质上是可逆的和非共价的。我们认为，这些有效的抗炎药物随pH变化进入磷脂双层，可能存在于粘液凝胶层的管腔界面上的细胞外单层/多层，可能导致这些膜和屏障的疏水性、流动性、通透性、生物力学性质和稳定性的深刻变化。这些变化不仅可能解释非类固醇抗炎药如何导致胃肠道粘膜表面损伤，作为导致消化性溃疡和出血的致病机制的一个组成部分，而且可能解释这一药物家族的一些(COX非依赖性)生物学作用。这一见解也被证明在设计和开发一类与PC相关的新型非类固醇抗炎药方面也很有用，这些药物降低了胃肠道毒性，同时保持了抑制疼痛和炎症的基本治疗效果。
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely consumed pharmaceuticals, yet both the mechanisms involved in their therapeutic actions and side-effects, notably gastrointestinal (GI) ulceration/bleeding, have not been clearly defined. In this study, we have used a number of biochemical, structural, computational and biological systems including; Fourier Transform InfraRed (FTIR). Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) spectroscopy, and cell culture using a specific fluorescent membrane probe, to demonstrate that NSAIDs have a strong affinity to form ionic and hydrophobic associations with zwitterionic phospholipids, and specifically phosphatidylcholine (PC), that are reversible and non-covalent in nature. We propose that the pH-dependent partition of these potent anti-inflammatory drugs into the phospholipid bilayer, and possibly extracellular mono/multilayers present on the luminal interface of the mucus gel layer, may result in profound changes in the hydrophobicity, fluidity, permeability, biomechanical properties and stability of these membranes and barriers. These changes may not only provide an explanation of how NSAIDs induce surface injury to the GI mucosa as a component in the pathogenic mechanism leading to peptic ulceration and bleeding, but potentially an explanation for a number of (COX-independent) biological actions of this family of pharmaceuticals. This insight also has proven useful in the design and development of a novel class of PC-associated NSAIDs that have reduced GI toxicity while maintaining their essential therapeutic efficacy to inhibit pain and inflammation.
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