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May 16, 2012
Antidepressant Drugs and Cell Membranes
How much do we really know about what small drug molecules do when they get into cells? Everyone involved in this sort of research wonders about this question, especially when it comes to toxicology. There's a new paper out in PLoS One that will cause you to think even harder.
The researchers (from Princeton) looked at the effects of the antidepressant sertraline, a serotonin reuptake inhibitor. They did a careful study in yeast cells on its effects, and that may have some of you raising your eyebrows already. That's because yeast doesn't even have a serotonin transporter. In a perfect pharmacological world, sertraline would do nothing at all in this system.
We don't live in that world. The group found that the drug does enter yeast cells, mostly by diffusion, with a bit of acceleration due to proton motive force and some reverse transport by efflux pumps. (This is worth considering in light of those discussions we were having here the other day about transport into cells). At equilibrium, most (85 to 90%) of the sertaline that makes it into a yeast cell is stuck to various membranes, mostly ones involved in vesicle formation, either through electrostatic forces or buried in the lipid bilayer. It's not setting off any receptors - there aren't any - so what happens when it's just hanging around in there?
More than you'd think, apparently. There's enough drug in there to make some of the membranes curve abnormally, which triggers a local autophagic response. (The paper has electron micrographs of funny-looking Golgi membranes and other organelles). This apparently accounts for the odd fact, noticed several years ago, that some serotonin reuptake inhibitors have antifungal activity. This probably applies to the whole class of cationic amphiphilic/amphipathic drug structures.
The big question is what happens in mammalian cells at normal doses of such compounds. These may well not be enough to cause membrane trouble, but there's already evidence to the contrary. A second big question is: does this effect account for some of the actual neurological effects of these drugs? And a third one is, how many other compounds are doing something similar? The more you look, the more you find. . .
+ TrackBacks (0) | Category: Drug Assays | Pharmacokinetics | The Central Nervous System | Toxicology
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