The Tarascon Pocket Pharmacopoeia is a compact medication reference book that I discovered long ago when I was in pharmacy school. The 2016 edition arrived today and while thumbing through it I was reminded how much I love biochemistry. We’ve learned a lot about the complex interplay of the chemical machinery of our bodies which has allowed us to develop drugs that treat disease and modify the function of our bodies. The primary component of these chemical machines are proteins. Proteins are made of amino acids that are linked together much like beads on a necklace. There are 22 different types of amino acids found in the human body. The type and sequence of these amino acids gives the protein strand a specific shape and function. This shape can change when it comes in contact with certain molecules (e.g. ATP) which allows the protein to perform work ranging from muscle movement to cellular pumps and gates.
One such pump is P-glycoprotein (P-gp), an efflux transporter found on the cell membrane that pumps drugs and other substances out of cells. The picture on this post shows its crystallographic structure (I think it’s kind of pretty). In the gut, P-gp reduces drug absorption by pumping drugs into the gut lumen. In the kidneys, it increases drug excretion by pumping drugs into urine. Some drugs induce or inhibit the action of P-gp. Inhibitors can increase exposure to P-gp substrates, potentially increasing their risk of toxicity. P-gp inducers can reduce exposure to P-gp substrates, potentially increasing the risk of treatment failure. This is a type of drug interaction – when one drug increases or decrease the action of another drug. It is just one of the numerous issues that pharmacists watch for when dispensing medication to patients or advising physicians on drug therapy.
P-glycoprotein has numerous functions some of which are cellular regulation, removal of toxic metabolites, migration of dendritic cells, and transport of compounds out of the brain across the blood–brain barrier, etc, etc. But one of the more onerous functions occurs in cancer cells when P-gp is over expressed and it transports chemotherapeutic agents out of the cell. This is the cause of some cancers becoming resistant to treatment (i.e. the chemo drug can’t work if it gets pumped out of the cancer cell). Hopefully more research will be done targeting this important but sometimes detrimental protein pump in the fight against cancer.
When I step back and look at all of the chemical reactions going on inside our body, I’m in awe of the beauty that I see. It’s one part musical symphony and one part jazz concert. The players act in a coordinated, concerted effort to deal with the randomness which is inherent in the system. It’s the music of life and I find it fascinating.
Here's a nice video that will give you a feel for the conformational changes that happen while the pump operates.https://youtu.be/T8dZwSPr8i8