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

Our previous study showed that insulin restored impaired function and expression of P-glycoprotein in diabetic blood-brain barrier, and further study showed that insulin up-regulated P-glycoprotein expression and function in normal blood-brain barrier, so insulin might be one of the factors that regulated the function and expression of P-glycoprotein in blood-brain barrier of diabetes. In this study, the intracellular pathways that insulin regulated the P-glycoprotein were investigated using primarily cultured rat brain microvessel endothelial cells model. The rat brain microvessel endothelial cells were incubated in normal culture medium containing 50 mU/l insulin and different concentrations of inhibitors for 72 h. The P-glycoprotein function and expression in the rat brain microvessel endothelial cells were assessed using the uptake of P-glycoprotein substrate rhodamine 123 and western blot assay, respectively. It was found that treatment of 50 mU/l insulin significantly increased P-glycoprotein function and expression in rat brain microvessel endothelial cells. This induced effect was blocked by insulin receptor antibody, insulin receptor tyrosine kinase inhibitor I-OMe-AG538, PKC inhibitor chelerythrine and NF-kappaB inhibitor pyrrolidine dithiocarbamate ammonium (PDTC). But this induced effect was not inhibited by phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002. These results indicated that insulin regulated P-glycoprotein function and expression through signal transduction pathways involving activation of PKC/NF-kappaB but not PI3K/Akt pathway.
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PMID:Insulin regulates P-glycoprotein in rat brain microvessel endothelial cells via an insulin receptor-mediated PKC/NF-kappaB pathway but not a PI3K/Akt pathway. 1904 3

Cynomolgus monkey has been used as a model for the prediction of drug disposition in human brain. The purpose of this study was to clarify protein expression levels of membrane proteins affecting drug distribution to brain, such as transporters, receptors, and junctional proteins, in cynomolgus monkey brain microvessels by using liquid chromatography tandem mass spectrometry. In adult monkeys, three ATP-binding cassette transporters (multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4)), six solute carrier transporters (glucose transporter 1 (GLUT1), GLUT3/14, monocarboxylate transporter 1 (MCT1), MCT8, organic anion transporting polypeptide 1A2, and equilibrative nucleoside transporter 1), two junctional proteins (claudin-5 and vascular endothelial cadherin), and two receptors (insulin receptor and low-density lipoprotein receptor-related protein 1) were detected. Comparison of the expression levels with those in mouse, which we reported previously, revealed a pronounced species difference. BCRP expression in monkey was greater by 3.52-fold than that in mouse, whereas MDR1 and MRP4 expression levels in monkey were lower by 0.304- and 0.180-fold, respectively, than that in mouse. This study also investigated the developmental changes in expression of membrane proteins in neonate and child monkeys. Expression of MDR1 was similar in neonate and adult monkeys, whereas in rat, P-glycoprotein expression was reported to be significantly lower in brain microvessels of neonate as compared with adult rat. These results will be helpful to understand and predict brain concentrations of drugs in different species and at different ages of primates.
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PMID:Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. 2125 69

Although lipid-rich microdomains of hepatocyte plasma membranes serve as the major scaffolding regions for cholesterol transport proteins important in cholesterol disposition, little is known regarding intracellular factors regulating cholesterol distribution therein. On the basis of its ability to bind cholesterol and alter hepatic cholesterol accumulation, the cytosolic liver type FA binding protein (L-FABP) was hypothesized to be a candidate protein regulating these microdomains. Compared with wild-type hepatocyte plasma membranes, L-FABP gene ablation significantly increased the proportion of cholesterol-rich microdomains. Lack of L-FABP selectively increased cholesterol, phospholipid (especially phosphatidylcholine), and branched-chain FA accumulation in the cholesterol-rich microdomains. These cholesterol-rich microdomains are important, owing to enrichment therein of significant amounts of key transport proteins involved in uptake of cholesterol [SR-B1, ABCA-1, P-glycoprotein (P-gp), sterol carrier binding protein (SCP-2)], FA transport protein (FATP), and glucose transporters 1 and 2 (GLUT1, GLUT2) insulin receptor. L-FABP gene ablation enhanced the concentration of SCP-2, SR-B1, FATP4, and GLUT1 in the cholesterol-poor microdomains, with functional implications in HDL-mediated uptake and efflux of cholesterol. Thus L-FABP gene ablation significantly impacted the proportion of cholesterol-rich versus -poor microdomains in the hepatocyte plasma membrane and altered the distribution of lipids and proteins involved in cholesterol uptake therein.
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PMID:Loss of liver FA binding protein significantly alters hepatocyte plasma membrane microdomains. 2222 61

To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials.
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PMID:MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor. 2353 32

The purpose of this study was to determine the protein amounts of blood-brain barrier (BBB) permeability-related transporters, receptors, and tight junction proteins in Sprague Dawley and Wistar rats and common marmoset, and also to investigate inter-species and inter-strain differences across rodents and primates. Quantification of target proteins in isolated brain capillaries was conducted by liquid chromatography-tandem mass spectrometry-based quantitative targeted absolute proteomics, with in silico peptide selection. Most target proteins showed inter-rodent, inter-primate species, and inter-rat strain differences of less than 2-fold. Comparison of rat and human BBB showed that P-glycoprotein, multidrug resistance-associated protein 4, monocarboxylate transporter 1, l-type amino acid transporter, and organic anion transporter 3 exhibited differences of more than two-fold in protein abundance, whereas the amounts of breast cancer resistance protein, glucose transporter 1, and insulin receptor were similar in rat and human. In contrast, the differences between marmoset and human BBB were less than 2-fold for almost all measured proteins. Thus, the molecular basis of BBB functions may be similar in marmoset and human, whereas that of rats shows significant differences. The marmoset may be a good model to access in vivo human BBB permeability characteristics, as an alternative to rat and macaque monkey.
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PMID:Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. 2365 Jan 39