P-glycoprotein

P-glycoprotein
Name	P-glycoprotein
AltSymbols	MDR1, PGY1
Organism	Homo sapiens
Band	21.12
EntrezGene	5243
OMIM	171050
RefSeq	NM_000927
UniProt	P08183

P-glycoprotein. It is a crucial ATP-binding cassette transporter that functions as an efflux pump, moving a wide variety of substrates out of cells. First identified in Chinese hamster ovary cells for its role in conferring resistance to chemotherapy drugs, its activity is a major mechanism in multidrug resistance. The protein is encoded by the ABCB1 gene in humans and is expressed in many tissues with barrier or excretory functions, such as the intestine, liver, kidney, and blood-brain barrier.

Structure and function

P-glycoprotein is a large, transmembrane protein belonging to the ABC transporter superfamily. Its structure, elucidated through techniques like X-ray crystallography and cryo-electron microscopy, consists of two homologous halves, each containing six transmembrane domains and a cytosolic nucleotide-binding domain. The protein undergoes conformational changes powered by ATP hydrolysis, transitioning between inward-facing and outward-facing states to transport substrates. This efflux mechanism is fundamental for the protective function of physiological barriers, actively pumping xenobiotics and metabolic products from cells into luminal spaces or the bloodstream for elimination. Its broad substrate specificity is attributed to a large, flexible binding pocket within the transmembrane domains.

Gene and expression

The human gene encoding this protein, ABCB1 (also historically called MDR1), is located on chromosome 7 at locus 7q21.12. The gene is highly polymorphic, with single-nucleotide polymorphisms like C3435T influencing expression levels and function. Its expression is regulated by various transcription factors, including the pregnane X receptor and the constitutive androstane receptor, which are activated by foreign compounds. Tissue-specific expression is prominent in the epithelial cells of the small intestine, the bile canaliculi of the liver, the proximal tubules of the kidney, and the capillary endothelial cells of the blood-brain barrier and placenta. This strategic localization underscores its role in absorption, distribution, metabolism, and excretion of drugs.

Role in multidrug resistance

The most studied role of this transporter is in multidrug resistance in cancer, particularly after the pioneering work of Victor Ling. It was discovered that overexpression in tumor cells leads to reduced intracellular accumulation of many chemotherapeutic agents, such as doxorubicin, vincristine, and paclitaxel. This efflux decreases drug efficacy, contributing to treatment failure in cancers like acute myeloid leukemia and ovarian carcinoma. Resistance extends beyond oncology; similar mechanisms are implicated in infectious disease, where pathogens like Plasmodium falciparum and Candida albicans utilize homologous transporters to expel antimicrobial drugs, complicating treatments for malaria and fungal infections.

Substrates and inhibitors

This transporter has an exceptionally broad and diverse substrate profile, encompassing many structurally unrelated compounds. Substrates include cytotoxic drugs, HIV protease inhibitors, cardiac glycosides like digoxin, immunosuppressants such as cyclosporine A, and many other pharmaceutical agents. Inhibitors are classified into three generations: first-generation agents like verapamil and cyclosporine A; second-generation analogs like valspodar; and third-generation, highly specific inhibitors including tariquidar and elacridar. These inhibitors are designed to block the pump's function and overcome multidrug resistance, though clinical success has been limited by toxicity and pharmacokinetic interactions.

Clinical significance

Its activity profoundly affects the pharmacokinetics and pharmacodynamics of many drugs. In the intestine, it limits the oral bioavailability of substrates. In the blood-brain barrier, it restricts central nervous system penetration, impacting treatments for epilepsy, brain tumors, and neurodegenerative diseases. In the liver and kidney, it facilitates biliary and urinary excretion. Genetic polymorphisms in the ABCB1 gene can lead to inter-individual variability in drug response and risk of adverse drug reactions. Furthermore, its expression in hematopoietic stem cells provides protection against toxins, a function exploited in gene therapy trials.

Research and therapeutic targeting

Research efforts, supported by institutions like the National Institutes of Health, focus on circumventing its role in drug resistance. Strategies include the development of novel pump inhibitors, nanoparticle-based drug delivery systems to bypass efflux, and the use of small interfering RNA to silence its expression. Clinical trials, such as those conducted by the Eastern Cooperative Oncology Group, have evaluated combinations of chemotherapeutics with inhibitors like tariquidar. Other avenues investigate its role in neurodegenerative diseases like Alzheimer's disease, where it may help clear amyloid-beta peptides from the brain. Understanding its regulation and transport cycle remains a key goal for improving drug efficacy across multiple therapeutic areas.

Category:Proteins Category:Cell biology Category:Oncology