It's well known that high doses of aspirin can cause ulcers and temporary deafness, but the biochemical mechanism responsible for these phenomena has never been deciphered.
New research from Rice University offers clues, showing for the first time how salicylate -- an active metabolite of aspirin -- weakens lipid membranes. Researchers believe these mechanical changes disrupt the lining of the stomach, which functions to protect underlying tissue from the acidic contents of the gut. By a similar mechanism, the changes may result in aspirin-related deafness by interfering with the proper function of prestin, a transmembrane protein that's critical for mammalian hearing.
The study appears in the September issue of Biophysical Journal.
"Our studies found that membranes exposed to physiological concentrations of salicylate were thinner, more permeable, easier to bend and more likely to rupture," said study co-author Robert Raphael, the T.N. Law Assistant Professor of Bioengineering.
All cells are surrounded by membranes, ultrathin barriers of fatty acids that are just a few nanometers thick. Membranes act like a skin, sealing off the inner machinery of the cell from the outside world. About 40 percent of human proteins are "transmembrane" proteins, molecules that stick through the membrane like a needle through a cloth.
First identified five years ago, prestin is a transmembrane protein found in the inner ear. A motor protein, prestin is thought to act like a piezocrystal, converting electrical signals into mechanical motion. In the outer hair cells of the cochlea, prestin acts as a molecular motor, causing the cells to move rhythmically and amplify the sounds we hear.
"If you change the mechanical properties of the membrane, you will likely affect the biophysical processes that take place there, including those that are mediated by membrane proteins like prestin," Raphael said.
Raphael's findings also provide a mechanistic basis for the observations of Texas Medical Center researchers who have found that the debilitating and dangerous gastrointestinal side-effects of anti-inflammatory drugs like aspirin and ibuprofen are independent of biochemical signaling cascades mediated by cyclo-oxygenase (COX). Raphael's research was co-sponored by the Texas Technology Development and Transfer Program and PLX Pharma, a Houston-based startup that began the final phase of clinical trials for its reformulated version of ibuprofen last December.
"Effectively, our results proved that salicylate can stabilize holes that spontaneously form in lipid membranes, thus increasing membrane permeability", Raphael said. "Our study highlights the pivotal role played by the mechanical properties of membranes in biological processes."
In their experiments, Raphael and graduate student Yong Zhou, the first author of the study, used a technique called micropipette aspiration. Working with needle-like glass capillary tubes, Zhou measured the mechanical properties of phospholipid membranes, which are very similar to those of live cells.
Raphael credited Zhou's initiative in applying new technology to the problem.
"Yong was the driving force for introducing the new technique of dynamic tension spectroscopy into my laboratory," Raphael said. "This enabled us to really get insight into the subtle details associated with the mechanism by which salicyalte affects membrane stability."
Zhou was recently awarded a Student Research Fellowship award from the American Gastroenterological Association to conduct studies on another salicylate-like molecule.