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Aspirin
Causes Ulcers And Hearing Loss
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."
Reference
Source 125
September
21, 2005
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