Effect of nonsteroidal anti-inflammatory drugs on the mechanical and electrical stability of phospholipid membranes

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dc.contributor.advisorRaphael, Robert M.en_US
dc.creatorZhou, Yongen_US
dc.date.accessioned2009-06-03T21:11:11Zen_US
dc.date.available2009-06-03T21:11:11Zen_US
dc.date.issued2007en_US
dc.description.abstractNon-steroidal anti-inflammatory drugs (NSAIDs) display powerful anti-inflammatory, analgesic and anti-pyretic activities. Serious side effects of NSAIDs, such as gastrointestinal (GI) bleeding and peptic ulcer disease, cause hospitalization and even death of many patients who take these drugs. This is thought to result from the ability of NSAIDs to induce a back-diffusion of luminal acids into GI tissues. NSAID-induced back-diffusion of luminal acids has both biochemical and biophysical aspects. The biochemical aspect of NSAID activity, i.e. the ability of NSAIDs to inhibit the enzyme cyclo-oxygenase, has been examined extensively. However, the biophysical aspect of NSAID cyto-toxicity, i.e. the ability of NSAIDs to directly induce proton permeation across a phospholipid layer covering the GI tract, is not well understood. In order to gain a deeper understanding of the cyto-toxicity of NSAIDs, the biophysical effect of NSAIDs on lipid membranes must be examined. The proton permeability of a phospholipid membrane depends on several factors: the packing of lipids, the membrane rigidity and deformability, the tendency for a membrane to form pores and the electrostatic properties of the membrane. We utilized a variety of experimental techniques, including micropipette aspiration of giant unilamellar vesicles, fluorescent spectroscopy and electrophoretic motility, to quantitatively characterize the effect of the sodium salt of salicylic acid, a classic anti-inflammatory agent, on mechanical and electrostatic properties of phospholipid membranes. We found that at near neutral pH, salicylate/salicylic acid decreases the bending stiffness of membranes composed of 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC) and induces pore formation. As the solution pH was lowered to simulate the condition in the GI tract, the packing stability of SOPC vesicles exposed to sodium salicylate was seriously disrupted and the membrane dipole potential was decreased significantly. Salicylate anions also alter the membrane interfacial charge distribution by partitioning into the membrane. Thus, both salicylic acid and salicylate anion partition into membranes and affect membrane mesoscopic properties that determine membrane ion permeability. The ability of salicylate/salicylic acid to induce membrane pores suggests that this anti-inflammatory agent increases the probability of protons permeating across a phospholipid layer in the GI tract. The larger membrane damage caused by salicylate/salicylic acid at acidic pHs correlates well with clinical findings of higher toxicity of these drugs at low stomach pHs. It further confirms that the NSAID-lipid interaction is crucial the integrity of the mucosa. Moreover, since membranes are intimately involved in many important cell functions, effects of salicylate/salicylic acid on membranes observed in this thesis have relevance beyond the GI tract.en_US
dc.format.extent262 p.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.callnoTHESIS BIOCHEM. 2007 ZHOUen_US
dc.identifier.citationZhou, Yong. "Effect of nonsteroidal anti-inflammatory drugs on the mechanical and electrical stability of phospholipid membranes." (2007) Diss., Rice University. <a href="https://hdl.handle.net/1911/20677">https://hdl.handle.net/1911/20677</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/20677en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectBiochemistryen_US
dc.subjectBiomedical engineeringen_US
dc.subjectBiophysicsen_US
dc.titleEffect of nonsteroidal anti-inflammatory drugs on the mechanical and electrical stability of phospholipid membranesen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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