Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endocrine disrupters such as sex hormone-like chemicals and the non-physiological ligands for aryl hydrocarbon receptor (AhR) exert many adverse biological effects. The ligands for AhR disturb gene expression downstream of the gene induced by estrogen receptor at a very low concentration. Thus, transepithelial transport and cellular accumulation of cortisol (COR) and estrogen as congeners of sex hormone-like chemicals, and 3,3',4,4'-tetrachlorobiphenyl (TeCB) as one of the ligands for AhR were examined in a monolayer of porcine kidney cells transfected with human P-glycoprotein (LLC-COL). The net basal-to-apical transport of COR increased in LLC-COL compared to that in the wild type cells (LLC-PKI) the same as in vinblastine, whereas the net transport of estradiol (EST) was not detected in either cell group. Though the diffusion transports of EST for both directions, basal-to-apical and apical-to-basal, were higher than that of COR, cellular accumulation of EST was higher than that of COR. Transepithelial transport of TeCB was very low and the net basal-to-apical transport was not detected, while it was highly accumulated in the epithelial cells. The accumulation was slightly higher in LLC-COL than in LLC-PKI at high dose.
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PMID:Transepithelial transport and cellular accumulation of steroid hormones and polychlorobiphenyl in porcine kidney cells expressed with human P-glycoprotein. 1200 83

The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit both brain penetration and oral bioavailability of many chemotherapy drugs. Although US Food and Drug Administration guidelines require that potential interactions of investigational drugs with P-gp be explored, often this information does not enter the literature. In response, we developed a high-throughput screen to identify substrates of P-gp from a series of chemical libraries, testing a total of 10,804 compounds, most of which have known mechanisms of action. We used the CellTiter-Glo viability assay to test library compounds against parental KB-3-1 human cervical adenocarcinoma cells and the colchicine-selected subline KB-8-5-11 that overexpresses P-gp. KB-8-5-11 cells were also tested in the presence of a P-gp inhibitor (tariquidar) to assess reversibility of transporter-mediated resistance. Of the tested compounds, a total of 90 P-gp substrates were identified, including 55 newly identified compounds. Substrates were confirmed using an orthogonal killing assay against human embryonic kidney-293 cells overexpressing P-gp. We confirmed that AT7159 (cyclin-dependent kinase inhibitor), AT9283, (Janus kinase 2/3 inhibitor), ispinesib (kinesin spindle protein inhibitor), gedatolisib (PKI-587, phosphoinositide 3-kinase/mammalian target of rampamycin inhibitor), GSK-690693 (AKT inhibitor), and KW-2478 (heat-shock protein 90 inhibitor) were substrates. In addition, we assessed direct ATPase stimulation. ABCG2 was also found to confer high levels of resistance to AT9283, GSK-690693, and gedatolisib, whereas ispinesib, AT7519, and KW-2478 were weaker substrates. Combinations of P-gp substrates and inhibitors were assessed to demonstrate on-target synergistic cell killing. These data identified compounds whose oral bioavailability or brain penetration may be affected by P-gp. SIGNIFICANCE STATEMENT: The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to be expressed at barrier sites, where it acts to limit oral bioavailability and brain penetration of substrates. In order to identify novel compounds that are transported by P-gp, we developed a high-throughput screen using the KB-3-1 cancer cell line and its colchicine-selected subline KB-8-5-11. We screened the Mechanism Interrogation Plate (MIPE) library, the National Center for Advancing Translational Science (NCATS) pharmaceutical collection (NPC), the NCATS Pharmacologically Active Chemical Toolbox (NPACT), and a kinase inhibitor library comprising 977 compounds, for a total of 10,804 compounds. Of the 10,804 compounds screened, a total of 90 substrates were identified of which 55 were novel. P-gp expression may adversely affect the oral bioavailability or brain penetration of these compounds.
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PMID:A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. 3151 84