3.A.1.201.1
Broad specificity multidrug resistance (MDR1; MDR-1; Pgp; P-gp; ABCB1; P-glycoprotein) efflux pump. It exports organic cations and amphiphilic compounds of unrelated chemical structure.  These include: antibiotics, anti-viral agents, cancer chemotheraputic agents, hypertensives, depressants, histamines, emetics, and the protease inhibitor, lopinavir. Pgp also exports immunosuppressants, detergents, long-chain fatty acids, HIV protease inhibitors, synthetic tetramethylrosamine analogues, calcein M, etc.); it is also a peptide efflux pump, and peptide inhibitors have been designed (Tarasova et al. 2005). It is also a phospholipid (e.g., phosphatidyl serine), cholesterol and sterol flippase. It binds and probably transports inhibitors and agonists of SUR (3.A.1.208.4) (Bessadok et al., 2011). Modulatory effects of inhibitory amlodipine and tamoxifen on P-glycoprotein efflux activities have been studied (Darvari and Boroujerdi 2004).  It is found in many tissues (intestine, kideny, blood brain barrier, liver, etc. (Wang et al. 2024). The 3-d structure has been determined (Aller et al., 2009). It can pump from the cytoplasmic leaflet to either the outer leaflet or the outer medium (Katzir et al., 2010). The inhibitor, 5''-fluorosulfonylbenzoyl 5''-adenosine, an ATP analogue, interacts with both drug-substrate- and nucleotide-binding sites (Ohnuma et al., 2011). Inhibited by sildenafil (Shi et al., 2011), verapamil, indomethacin, probenecid, cetirizine (He et al. 2010), and lapatinib derivatives (Sodani et al., 2012), several of which are also substrates. HG-829 is a potent non-competitive inhibitor (Caceres et al., 2012).  Berberine, palmatine, jateorhizine, cetirizine and coptisine are all P-gp substrates, and cyclosporin A and verapamil are potent inhibitors (He et al. 2010; Zhang et al., 2011).  Transports clarithromycin (CAM), a macrolide antibiotic used to treat lung infections, more effectively than azithromycin (AZM) or telithromycin (TEL) (Togami et al. 2012).  Nucleotides, lipids and drugs bind synergistically to the pump (Marcoux et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  The central cavity undergoes alternating access during ATP hydrolysis (van Wonderen et al. 2014).  Structural data suggest that signals are transduced through intracellular loops of the TMSs that slot into grooves on the NBDs. The Q loops at the base of these grooves are required to couple drug binding to the ATP catalytic cycle of drug export (Zolnerciks et al. 2014). Ocotillol analogues are strong competitive inhibitors (Zhang et al. 2015).  Durmus et al. 2015 have reviewed PGP transport of cancer chemotheraputic agents.  ABCB1 variants modulate therapeutic responses to modafinil and may partly explain pharmacoresistance in Narcolepse type 1 (NT1) patients (Moresco et al. 2016).  Many inhibitors have been identified (Hemmer et al. 2015).  The open-and-close motion of the protein alters the surface topology of P-gp within the drug-binding pocket, explaining its polyspecificity (Esser et al. 2016). The ATP- and substrate-coupled conformational cycle of the mouse Pgp transporter have been defined, showing that the energy released by ATP hydrolysis is harnessed in the NBDs in a two-stroke cycle (Verhalen et al. 2017).  Rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport (Reznicek et al. 2017).  It transports Huerzine A in the brain, a drug that is used for the treatment of Alzheimer's disease (Li et al. 2017). AbcB1 acts in concert with ABCA1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018).The structure has been determined with the ABCB1 inhibitor, zosuquidar, bound.  This structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all TMSs. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules (Alam et al. 2018).  Iit is also inhibited by dacomitinib (Fan et al. 2018). Moreover, Kim and Chen 2018 presented the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-Å resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and is compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release (Kim and Chen 2018). P-gp also transports opioid peptides (Ganapathy and Miyauchi 2005). MDR1 has been quantified in primary human renal cell carcinoma cells and corresponding normal tissue, and down-regulation or expression loss was documented in tumor tissues, corroborating its importance in drug resistance and efficacy (Poetz et al. 2018). Regarding the conformational transitions, first the transition is driven by the NBDs, then transmitted to the cytoplasmic parts of TMSs, and finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement (Zhang et al. 2018). Isoxanthohumol is a substrate and competitive inhibitor which reverses ABCB1-mediated doxorubicin resistance (Liu et al. 2017). Tariquidar is a potent inhibitor, even when taken orally (Matzneller et al. 2018). Combined oral administration of the ovarian hormones, ethinyl estradiol and progesterone, significantly lowered both MDR-1 mRNA and MDR-1 protein in the ovary (Brayboy et al. 2018). Its expression in immune cells plays a protective role from xenobiotics and toxins (Bossennec et al. 2018). Oxypeucedanin reverses P-gp-mediated drug transport by inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA levels (Dong et al. 2018). Alam et al. 2019 determined the 3.5-Å cryo-EM structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the ATP-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport (Alam et al. 2019). The TMS4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp (Xing et al. 2019). The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by ABCB1 (Wen et al. 2019). Substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites, but this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites (Dastvan et al. 2019). It transports temozolomide (TMZ) which is used as a treatment of glioblasomas (Malmström et al. 2019). Unconventional cholesterol translocation on the surface of Pgp provides a secondary transport model for the known flippase activity of ABC exporters of cholesterol (Thangapandian et al. 2020). An in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp has been developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds) (Mora Lagares et al. 2019).  Jervine is a natural teratogenic compound isolated from Veratrum californicum. Liu et al. 2019 showed that jervine sensitizes the anti-proliferation effect of doxorubicin (DOX) and that the synergistic mechanism was related to the intracellular accumulation of DOX via modulating ABCB1 transport. Jervine did not affect the expression of ABCB1 in mRNA or protein levels. However, jervine increased the ATPase activity of ABCB1 and probably served as a substrate of ABCB1. Jervine binds to a closed ABCB1 conformation and blocks drug entrance to the central binding site at the transmembrane domain (Liu et al. 2019). 6-Triazolyl-substituted sulfocoumarins inhibit P-gp (Podolski-Renić et al. 2019). ATP binding causes the conformational change to the outward-facing state, and ATP hydrolysis and subsequent release of γ-phosphate from both NBDs allow the outward-facing state to return to the original inward-facing state (Futamata et al. 2020). Replacing the eleven native tryptophans by directed evolution produces an active P-glycoprotein with site-specific, non-conservative substitutions (Swartz et al. 2020). ABCB1 polymorphisms alter P-gp-mediated drug (sunitinib) sensitivities. Homology modeling provided insight into ligand binding through molecular docking studies (Mora Lagares et al. 2020). Sitravatinib  reverses MDR mediated by ABCB1 and partially antagonized ABCC10-mediated MDR (Yang et al. 2020). Apiole from parsley blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents (Afonso de Lima et al. 2020). The mechanisms of action of synthetic, potent, small molecule P-gp inhibitors have been reviewed (Zhang et al. 2020). ATP binding to the open NBDs and ATP hydrolysis in the closed NBD dimer represent two steps of energy input, each leading to the formation of a high energy state. Relaxation from these high energy states occurs through conformational changes that push ABCB1 through the transport cycle (Szöllősi et al. 2020). 14 conserved residues (seven in both TMsSs 6 and 12) were substituted with alanine and generated a mutant termed 14A (Sajid et al. 2020). Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, it was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, uptake was ATP hydrolysis-, substrate concentration-, and time-dependent. Further mutagenesis identified residues in both TMSs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell (Sajid et al. 2020). Helix repacking may be the basis for P-glycoprotein promiscuity (Bonito et al. 2020). The use of carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein has been shown to overcome cancer drug resistance (Wang et al. 2021). A sequentially responsive Nnanosystem breaches cascaded bio-barriers and suppresses P-Glycoprotein function for reversing cancer drug resistance (Liu et al. 2020). Lys-268 and the cytoplasmic end of TMS5 may comprise a drug binding site (Demmer et al. 2021). MDR1 protein (ABC-C1) is overexpressed in Giardia intestinalis following incubation with the drugs, albendazole and nitazoxanide (Ángeles-Arvizu et al. 2021). The human P-gp is inhibited by benzophenone sulfonamide derivatives (Farman et al. 2020) and androstano-arylpyrimidines (Gopisetty et al. 2021), and possibly by tepoxalin (McQuerry et al. 2021). The inward facing state of P-glycoprotein in a lipid membrane has been confirmed (Carey Hulyer et al. 2020). For transmembrane pharmaceutical drug transport, non-specific trans-phospholipid bilayer transport may be negligible (Kell 2021). Glabratephrin reverses doxorubicin resistance in triple negative breast cancer by inhibiting P-glycoprotein (Abd-Ellatef et al. 2021). In silico screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 are potential MDR reversal agents (Moosavi et al. 2022). Quercetin acts as a P-gp modulator via impeding signal transduction from the nucleotide-binding domain to the transmembrane domain (Singh et al. 2022). MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells and exports the antiseizure drug, levetiracetam (Behmard et al. 2022). Air pollution exposure increases ABCB1 and ASCT1 transporter levels in mouse cortex (Puris et al. 2022). MDR-1 dysfunction perturbs meiosis and Ca²⁺ homeostasis in oocytes (Nabi et al. 2022). The P-glycoprotein (ABCB1) transporter has been modelled with in silico methods (Mora Lagares and Novič 2022). A new ABCB1 inhibitor enhances the anticancer effect of doxorubicin in models of non-small cell lung cancer (NSCLC) (Adorni et al. 2023). A homologous series of amphiphiles interact with P-glycoprotein in a membrane environment, and the contributions of polar and non-polar interactions has been estimated (Moreno et al. 2023). TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. In taxane-resistant MCF-7 sublines, TRIP6 co-amplifies with the neighboring ABCB1 gene (Daniel et al. 2023). Inhibition of Cryptosporidium parvum by nitazoxanide (NTZ) and paclitaxel (PTX) has been validated (Yang et al. 2023). New inhibitors of ABCB1 have been identified (Cheema et al. 2023). Inhibitors of MDR pumps (MDR1, MRP1/2 and BCRP) have been described (Kaproń et al. 2023). A hyaluronic acid modified cuprous metal-organic complex reverses multidrug resistance via redox dyshomeostasis (Wan et al. 2023; Duan et al. 2023). The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface (Seelig and Li-Blatter 2023). ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade >/=3 infections (Ferrero et al. 2023). Wine-processed Chuanxiong Rhizoma enhances the efficacy of aumolertinib against EGFR mutant non-small cell lung cancer xenografts in nude mouse brain (Niu et al. 2023). The efflux of anti-psychotics through the blood-brain barrier (BBB) via this system has been demonstrated (Nasyrova et al. 2023). Residues from homologous TMSs 4 and 10 are critical for P-glycoprotein (ABCB1)-mediated drug transport (Rahman et al. 2023). Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse MDR (Ibrahim et al. 2023). Other substrates and inhibitors from Anemarrhenae rhizoma have been identified (Dai et al. 2022).  Peptides and their analogs can cross the BBB by transmembrane diffusion, saturable transport, and adsorptive transcytosis (Banks 2023). Saturable transport systems are adaptable to physiologic changes and can be altered by disease states. In particular, transport across the BBB of insulin and of pituitary adenylate cyclase activating polypeptide (PACAP) illustrate many of the concepts regarding peptide transport across the BBB (Banks 2023).  Second-site suppressor mutations reveal connections between the drug-binding pocket and the nucleotide-binding domain 1 of human P-glycoprotein (ABCB1) (Murakami et al. 2023).  Betulin derivatives are multidrug reversal agents targeting P-glycoprotein (Laiolo et al. 2024). Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance (Xu et al. 2024). One can overcome ABCB1-mediated multidrug resistance in castration resistant prostate cancer cases (Sarwar et al. 2024). Pyridoquinoxaline-based P-gp inhibitors are coadjutant against Multi Drug Resistance in cancer (Ibba et al. 2024). Lansoprazole (LPZ) reverses multidrug resistance in cancer through impeding ABCB1 and ABCG2 transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration (Ji et al. 2024). N,N-dimethyl-idarubicin analogues are effective cytotoxic agents for ABCB1-overexpressing, doxorubicin-resistant cells (van Gelder et al. 2024).  Anthranilamide derivatives are dual P-glycoprotein and CYP3A4 (see TC# 9.B.208) inhibitors (Said et al. 2024).  FRα and multiple transporters such as PCFT, RFC, OAT4, and OATPs are likely involved in the uptake of methotraxate (MTX), whereas MDR1 and BCRP are implicated in the efflux of MTX from choriocarcinoma cells (Bai et al. 2024). Sofosbuvir (SOF) is a P-glycoprotein (P-gp) substrate, and carvedilol (CAR) is an inhibitor of P-gp (Fahmy et al. 2024). The effect of ABCB1 polymorphisms on the accumulation of bictegravir has been studied (De Greef et al. 2024). Two other substrates of P-gp are digoxin and paclitaxel (Volpe 2024). ABCB1 transcripts are readily traceable in the liquid-biopsy of ovarian cancer patients (Schwarz et al. 2024). Quinolinone-pyrimidine hybrids are reversal agents of multidrug resistance mediated by P-gp (Laiolo et al. 2021).  Borneol promotes berberine-induced cardioprotection in a rat model of myocardial ischemia/reperfusion injury by inhibiting P-glycoprotein expression (Pan et al. 2024).  Mutational analysss revealed the importance of residues in the access tunnel inhibitor site to human P-glycoprotein-mediated transport (Salazar et al. 2024). P-glycoprotein inhibitors may help in the targeted delivery of anti-cancer drugs (Patel et al. 2024).