ABCB1 генінің экспрессиясы және оның Homo sapiens-тегі функциясы

Mammalian protein found in Homo sapiens

ABCB1 at EBI Gene Expression Atlas ABCB1 is differentially expressed in 97 experiments [93 up/106 dn]: 26 organism parts: kidney [2 up/0 dn], bone marrow [0 up/2 dn], ; 29 disease states: normal [10 up/3 dn], glioblastoma [0 up/2 dn], ; 30 cell types, 22 cell lines, 11 compound treatments and 16 other conditions. Factor Value Factor Up/Down Legend: – number of studies the gene is up/down in Normal Disease state 10/3None Compound treatment 3/0Stromal cell Cell type 1/2Kidney Cell type 2/0MDA MB 231 Cell line 0/2Glioblastoma Disease state 0/2Epithelial cell Cell type 0/2HeLa Cell line 0/2Primary Disease staging 2/0Bone marrow Organism part 0/2 ABCB1 expression data in ATLAS

P glycoprotein 1 (permeability glycoprotein, abbreviated as P gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP binding cassette sub family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP dependent efflux pump with broad substrate specificity. It exists in animals, fungi, and bacteria, and it likely evolved as a defense mechanism against harmful substances. P gp is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urinary filtrate (in the proximal tubule), and in the capillary endothelial cells composing the blood–brain barrier and blood–testis barrier, where it pumps them back into the capillaries. P gp is a glycoprotein that in humans is encoded by the ABCB1 gene. P gp is a well characterized ABC transporter (which transports a wide variety of substrates across extra and intracellular membranes) of the MDR/TAP subfamily. The normal excretion of xenobiotics back into the gut lumen by P gp pharmacokinetically reduces the efficacy of some pharmaceutical drugs (which are said to be P gp substrates). In addition, some cancer cells also express large amounts of P gp, further amplifying that effect and rendering these cancers multidrug resistant. Many drugs inhibit P gp, typically incidentally rather than as their main mechanism of action; some foods do as well. Any such substance can sometimes be called a P gp inhibitor. P gp was discovered in 1971 by Victor Ling.

A 2015 review of polymorphisms in ABCB1 found that "the effect of ABCB1 variation on P glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e. g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance."

P gp is a 170 kDa transmembrane glycoprotein, which includes 10 15 kDa of N terminal glycosylation. The N terminal half of the protein contains 6 transmembrane helixes, followed by a large cytoplasmic domain with an ATP binding site, and then a second section with 6 transmembrane helixes and an ATP binding domain that shows over 65% of amino acid similarity with the first half of the polypeptide. In 2009, the first structure of a mammalian P glycoprotein was solved (3G5U). The structure was derived from the mouse MDR3 gene product heterologously expressed in Pichia pastoris yeast. The structure of mouse P gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X) that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P gp is lined with aromatic amino acid side chains. Through Molecular Dynamic (MD) simulations, this sequence was proved to have a direct impact in the transporter's structural stability (in the nucleotide binding domains) and defining a lower boundary for the internal drug binding pocket.

P gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum. P gp is also found in brain capillary endothelial cells.

At the transcriptional level, the expression of P gp has been intensively studied, and numerous transcription factors and pathways are known to play roles. A variety of transcription factors, such as p53, YB 1, and NF κB are involved in the direct regulation of P gp by binding to the promoter regions of the P gp gene. Many cell signaling pathways are also involved in transcriptional regulation of P gp. For example, the PI3K/Akt pathway were reported to positively regulate the expression of P gp. Mitogen activated protein kinase (MAPK) signaling includes three pathways: the classical MAPK/ERK pathway, the p38 MAPK pathway, and the c Jun N terminal kinase (JNK) pathway, all of which were reported to have implications in the regulation of the expression of P gp. Studies suggested that the MAPK/ERK pathway is involved in the positive regulation of P gp; the p38 MAPK pathway negatively regulates the expression of the P gp gene; and the JNK pathway was reported to be involved in both positive regulation and negative regulation of P gp. After 2008, microRNAs (miRNAs) were identified as new players in regulating the expression of P gp in both transcriptional and post transcriptional levels. Some miRNAs decrease the expression of P gp. For example, miR 200c down regulates the expression of P gp through the JNK signaling pathway miR 145 down regulates the mRNA of P gp by directly binding to the 3' UTR of the gene of P gp and thus suppresses the translation of P gp. Some other miRNAs increase the expression of P gp. For example, miR 27a up regulates P gp expression by suppressing the Raf kinase inhibitor protein (RKIP); alternatively, miR 27a can also directly bind to the promoter of the P gp gene, which works in a similar way with the mechanism of action of transcriptional factors. The expression of P gp is also regulated by post translational events, such as post transcriptional modification, degradation, and intracellular trafficking of P gp. Pim 1 protects P gp from ubiquitination and the following degradation in the proteasome. Small GTPases Rab5 down regulates the endocytotic trafficking of P gp and thus increases the functional P gp level on the cell membrane; while Small GTPases Rab4 work in an opposite way: Rab4 down regulates the exocytotic trafficking of P gp from intracellular compartments to the cell membrane, and therefore decreases the functional P gp level on the cell membrane.

Some common pharmacological inhibitors of P glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, and duloxetine. Elacridar and CP 100356 are other common P gp inhibitors. Zosuquidar and tariquidar were also developed with this in mind. Lastly, valspodar and reversan are other examples of such agents. ABCB1 is linked to the daily dose of warfarin required to maintain the INR to a target of 2.5. Patients with the GT or TT genotypes of the 2677G>T SNP require around 20% more warfarin daily. Common pharmacological inducers of P glycoprotein include carbamazepine, dexamethasone, doxorubicin, nefazodone, phenobarbital, phenytoin, prazosin, rifampicin, St. John's wort, tenofovir, tipranavir, trazodone, and vinblastine. Substrates of P glycoprotein are susceptible to changes in pharmacokinetics due to drug interactions with P gp inhibitors or inducers. Some of these substrates include colchicine, ciclosporin, dabigatran, fexofenadine, indinavir, morphine, and sirolimus. Altered P gp function has also been linked to inflammatory bowel diseases (IBD); however, due to its ambivalent effects in intestinal inflammation many questions remain so far unanswered. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD.

P gp efflux activity is capable of lowering intracellular concentrations of otherwise beneficial compounds, such as chemotherapeutics and other medications, to sub therapeutic levels. Consequently, P gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance in human multidrug resistant (MDR) cancers.

P gp was first characterized in 1976. P gp was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs. The structure of mouse P gp, which has 87% sequence identity to human P gp, was resolved by x ray crystallography in 2009.

Radioactive verapamil can be used for measuring P gp function with positron emission tomography. P gp is also used to differentiate transitional B cells from naive B cells. Dyes such as rhodamine 123 and MitoTracker dyes from Invitrogen can be used to make this differentiation.

It has been suggested that MDR1 inhibitors might treat various diseases, especially cancers, but none have done well in clinical trials.

Single Nucleotide Polymorphism are important for the differential activity of the PGP pump. Homozygous subjects, identified with the TT genotype, are usually more able to extrude xenobiotics from the cell. A Homozygous genotype for the allele ABCB1/MDR1 is capable of a higher absorption from the blood vessels and a lower extrusion into the lumen. Xenobiotics are extruded at a lower rate with heterozygous (CT) alleles compared to homozygous ones.