title: Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine.
abstract: 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.
authors.affiliation: Department of Integrative Biology & Pharmacology, The Institute of Molecular Medicine, The University of Texas Health Science Center at Houston. lenard.m.lictenberger@uth.tmc.edu
authors.forename: Lenard M
authors.initials: LM
authors.lastname: Lichtenberger
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Jayaraman
authors.forename: Janice R
authors.initials: JR
authors.lastname: Doyen
authors.forename: Roger G
authors.initials: RG
authors.lastname: O'Neil
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Dial
authors.forename: David E
authors.initials: DE
authors.lastname: Volk
authors.forename: David G
authors.initials: DG
authors.lastname: Gorenstein
authors.forename: Mohan Babu
authors.initials: MB
authors.lastname: Boggara
authors.forename: Ramanan
authors.initials: R
authors.lastname: Krishnamoorti
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001241:Aspirin / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D005456:Fluorescent Dyes; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007052:Ibuprofen / Q000737:chemistry* / Q000494:pharmacology; D008051:Lipid Bilayers / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009288:Naproxen / Q000737:chemistry* / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry*; D011726:Pyridinium Compounds; D017550:Spectroscopy, Fourier Transform Infrared; D020349:Surface Plasmon Resonance
chemical_list: C089669:1-(3-sulfonatopropyl)-4-(beta-(2-(di-n-octylamino)-6-naphthyl)vinyl)pyridinium betaine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005456:Fluorescent Dyes; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D011726:Pyridinium Compounds; D009288:Naproxen; D001241:Aspirin; D007052:Ibuprofen