The new observations of the Warwick researchers suggest that the real transport rates could be up to a hundred times slower than predicted by the century old "Overton's Rule". This could have major implications for the development and testing of many future drugs.
Overton's rule says that the easier it is for a chemical to dissolve in a lipid (fat) the easier and faster it will be transported into a cell. The Rule was first outlined in the 1890s by Ernst Overton of the University of Zürich. He declared that substances that dissolve in lipids pass more easily into a cell than those that dissolve in water. He then set forth an equation that predicted how fast that diffusion would happen. One of the key parameters in that equation is K which defines the lipophilicity (oil-liking nature) of the chemical. The higher the value of K, the faster the predicted cell permeation rate. For over a century, medicinal chemists have used this relationship to shape their studies and clinical trials.
A team of electrochemists from the University of Warwick used a combination of a confocal microscope and an ultramicroelectrode to study what really happens when a chemical crosses a cell membrane. Advances in technology enabled them to position an ultramicroelectrode incrediblely close to the membrane boundary (roughly 20 microns away; ca. 1/3rd the thickness of a human hair) where it was used to generate a range of acids that should be able to diffuse relatively easily into a cell. These techniques allowed every step of the diffusion process to be directly examined. Previous studies had not been able to observe every step of the process and often required artificial stirring of the solutions.
The results stunned the researchers. While the acids did diffuse across a lipid membrane, they did so at rates that were diametrically opposite to the predictions of the Rule, i.e. the most lipophilic molecules were actually transported slowest. The researchers studied four acids (acetic, butanoic, valeric, and hexanoic) that had increasingly larger "acyl" (or carbon) chains. The longer the carbon chain, the easier the chemical dissolves in lipids and, therefore, according to Overton, the faster they should diffuse across a lipid membrane. In fact, the University of Warwick researchers observed that for these four acids the exact opposite is true: the easier it is for an acid to dissolve in a lipid, the slower it is transported across the membrane.
The research team will now use their technique to examine the diffusion into cells of a range of other chemicals. The lead researcher on the study from the University of Warwick, Professor Patrick Unwin, said:
"This was a surprising and exciting finding. Our direct observations appear to totally undermine a key rule that has withstood the test of time for over a century. We will now make observations with a range of other chemicals, and with other techniques, to further elucidate the molecular basis for our observations. Text books will have to be rewritten to revise a rule that has been relied on for over a century. Advanced techniques, such as the one we have developed, should give much clearer insight into the action of a wide range of drug molecules, which will be of significant interest to drug developers."
Professor Patrick Unwin | EurekAlert!
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine