P-glycoprotein, often shortened to P-gp, is a protein found in human cell membranes. It functions as a specialized “pump” that actively moves substances, pushing compounds out of cells.
Understanding P-glycoprotein
P-glycoprotein is formally known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1). It is an ATP-dependent efflux pump, using energy from ATP to actively transport substances out of cells. This transmembrane protein is embedded within the cell membrane, composed of two symmetrical halves, each with six transmembrane domains and a nucleotide-binding domain.
P-gp is widely distributed throughout the body, playing a role in various tissues and organs. It is found in the lining of the intestines, in liver cells where it pumps substances into bile ducts, and in kidney cells where it moves compounds into urinary filtrate. It is also present within the capillary endothelial cells that form the blood-brain barrier. In these areas, P-gp acts as a protective barrier, limiting the entry and promoting the removal of compounds from sensitive tissues.
P-glycoprotein’s Role in the Body
The primary physiological function of P-glycoprotein is to serve as a protective mechanism for the body. It actively expels harmful substances, toxins, and waste products from cells and tissues, preventing their accumulation. This role helps maintain cellular balance and overall health.
P-gp contributes to the integrity of various physiological barriers. For instance, at the blood-brain barrier, it prevents many substances, including potential toxins and certain drugs, from entering the brain, thereby protecting the central nervous system. In the gut, P-gp limits the absorption of potentially harmful compounds from the intestinal lumen into the bloodstream, directing them back out of the body. This protective action also extends to other areas like the blood-testis barrier and placenta, safeguarding sensitive organs and developing life.
P-glycoprotein and Medications
P-glycoprotein influences how medications are handled by the body, affecting their absorption, distribution, and elimination. In the intestines, P-gp acts as an efflux pump, transporting orally administered drugs back into the gut lumen, which can reduce the amount of drug absorbed into the bloodstream and thus lower its oral bioavailability. In the liver and kidneys, P-gp contributes to the removal of drugs from the body by pumping them into bile and urine for excretion.
The presence of P-gp at the blood-brain barrier also means it can prevent many drugs from reaching the brain, impacting the effectiveness of treatments for neurological disorders. P-gp’s involvement in multidrug resistance (MDR), particularly in cancer chemotherapy, is a concern in medicine. Cancer cells can overexpress P-glycoprotein, effectively pumping out chemotherapy drugs before they can act, rendering treatments ineffective. This phenomenon, where cancer cells develop resistance to a broad range of structurally different drugs, presents a challenge in oncology. Overexpression of P-gp has been detected in various chemoresistant cancers, including breast cancer, liver cancer, and lung cancer.
Modulating P-glycoprotein Activity
The activity of P-glycoprotein can be influenced by various substances, leading to changes in drug response. Certain medications, herbal supplements, and even dietary components like grapefruit juice can either inhibit (block) or induce (increase) P-gp’s activity. For example, inhibitors like verapamil can increase the absorption and concentration of P-gp substrate drugs, potentially leading to increased effectiveness or side effects. Conversely, inducers such as rifampicin or St. John’s wort can decrease the bioavailability of certain drugs by increasing P-gp activity, which might reduce their therapeutic effect.
Genetic variations in the ABCB1 gene (which encodes P-glycoprotein) can also affect its function, leading to individual differences in how people respond to medications. While numerous genetic variants have been identified, their effects on P-gp expression and activity can be small and inconsistent across various tissues. Despite extensive research, current knowledge of these genetic variations does not consistently allow for predicting an individual’s pharmacokinetics or for specific drug dosing adjustments based solely on ABCB1 gene variants.