First Insight into the Symmetry and Flexibility of Membrane Efflux Pump P-Glycoprotein by Novel Bifunctional Modulators

ChemBioChem ◽  
2005 ◽  
Vol 6 (8) ◽  
pp. 1353-1356 ◽  
Author(s):  
Jörg Wollmann ◽  
Martin Richter ◽  
Jósef Molnár ◽  
Andreas Hilgeroth
Keyword(s):  
Efflux Pump ◽  
P Glycoprotein ◽  
Insight Into

scholarly journals Human P-glycoprotein differentially affects antidepressant drug transport: relevance to blood–brain barrier permeability

2013 ◽  
Vol 16 (10) ◽  
pp. 2259-2272 ◽  
Author(s):  
Fionn E. O'Brien ◽  
Gerard Clarke ◽  
Timothy G. Dinan ◽  
John F. Cryan ◽  
Brendan T. Griffin
Keyword(s):  
Drug Transport ◽  
Efflux Pump ◽  
Antidepressant Drug ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Brain Barrier Permeability ◽  
Antidepressant Imipramine ◽  
Bidirectional Transport ◽  
Insight Into

Abstract The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) ⩾ 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P-gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR ⩽ 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp.

P-glycoprotein efflux pump expression and activity in Calu-3 cells

2001 ◽  
Vol 90 (5) ◽  
pp. 645
Author(s):  
Karen O. Hamilton ◽  
Gunilla Backstrom ◽  
Mehran A. Yazdanian ◽  
Kenneth L. Audus
Keyword(s):  
Efflux Pump ◽  
P Glycoprotein ◽  
Expression And Activity

scholarly journals Acute pain alters P-glycoprotein-containing protein complexes in rat cerebral microvessels: Implications for P-glycoprotein trafficking

2018 ◽  
Vol 38 (12) ◽  
pp. 2209-2222 ◽  
Author(s):  
Margaret E Tome ◽  
Chelsea K Jarvis ◽  
Charles P Schaefer ◽  
Leigh M Jacobs ◽  
Joseph M Herndon ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Protein Complexes ◽  
Activity Increase ◽  
Cerebral Microvessels ◽  
Cns Drug Delivery ◽  
Therapeutic Drugs ◽  
P Glycoprotein ◽  
Cell Plasma ◽  
Rat Paw ◽  
Major Drug

P-glycoprotein (PgP) is the major drug efflux pump in human cerebral microvessels. PgP prevents pathogens, toxins and therapeutic drugs from entering the CNS. Understanding the molecular regulation of PgP activity will suggest novel mechanisms to improve CNS drug delivery. Previously, we found that during peripheral inflammatory pain (PIP) (3 h after λ carrageenan injection in the rat paw), PgP traffics to the cortical microvessel endothelial cell plasma membrane concomitant with increased PgP activity. In the current study, we measured the changes in composition of PgP-containing protein complexes after PIP in rat microvessel isolates. We found that a portion of the PgP is contained in a multi-protein complex that also contains the caveolar proteins CAV1, SDPR, PTRF and PRKCDBP. With PIP, total CAV1 bound to PgP was unchanged; however, phosphorylated CAV1 (Y14P-CAV1) in the complex increased. There were few PgP/CAV1 complexes relative to total PgP and CAV1 in the microvessels suggesting CAV1 bound to PgP is unlikely to affect total PgP activity. However, both PgP and CAV1 trafficked away from the nucleus in response to PIP. These data suggest that P-CAV1 bound to PgP potentially regulates PgP trafficking and contributes to the acute PgP activity increase after a PIP stimulus.

P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells

Life Sciences ◽  
1992 ◽  
Vol 51 (18) ◽  
pp. 1427-1437 ◽  
Author(s):  
Akira Tsuji ◽  
Tetsuya Terasaki ◽  
Yasushi Takabatake ◽  
Yoshiyuki Tenda ◽  
Ikumi Tamai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Efflux Pump ◽  
Bovine Brain ◽  
Drug Efflux ◽  
Brain Capillary ◽  
Brain Capillary Endothelial Cells ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
Drug Efflux Pump

Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus Nor A efflux pump

2015 ◽  
Vol 13 (19) ◽  
pp. 5424-5431 ◽  
Author(s):  
Jaideep B. Bharate ◽  
Samsher Singh ◽  
Abubakar Wani ◽  
Sadhana Sharma ◽  
Prashant Joshi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Efflux Pump ◽  
Dual Inhibitor ◽  
P Glycoprotein ◽  
Dual Inhibition ◽  
And Staphylococcus Aureus

Pyrroles showed dual inhibition of human P-gp and S. aureus Nor A efflux pump.

scholarly journals P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 490-495 ◽  
Author(s):  
TM Grogan ◽  
CM Spier ◽  
SE Salmon ◽  
M Matzner ◽  
J Rybski ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Plasma Cells ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Significant Variable ◽  
Prior Chemotherapy ◽  
Prior Therapy ◽  
P Glycoprotein ◽  
Immunocytochemical Assay ◽  
Low Incidence

Abstract Multidrug-resistant (MDR) myeloma patients failing chemotherapy may express P-glycoprotein (PGP), which serves as an efflux pump protecting the neoplastic cells. Unknown is whether PGP expression might relate to prior cytotoxic drug exposure. To address this question, we studied 106 consecutive bone marrow samples from 104 myeloma patients with samples studied either before or after therapy and at the time of relapse. We performed an established immunocytochemical assay of PGP using an MDR-1- specific monoclonal antibody and correlated PGP status with prior chemotherapy dosage. Myeloma patients with no prior therapy had a low incidence of PGP expression (6%, 3/47), whereas those receiving chemotherapy had a significantly higher incidence (43%, 21/49) (P < .0001). A substantially higher incidence of PGP expression (50%, 83%, respectively) occurred when the total vincristine dose exceeded 20 mg and when doxorubicin exceeded 340 mg. In the 11 patients who received both high vincristine and doxorubicin dosages (> 20 mg, > 340 mg total dose) there was 100% incidence of PGP expression in the tumor cells. These data provided the basis for a predictive mathematical model from which dose-related PGP expression normograms were generated. Time with myeloma for PGP-negative patients (mean 33 months) had overlapping confidence limits with PGP-positive patients (mean 42 months), suggesting that disease duration was not a significant variable. PGP expression did not correlate with other clinical factors or immunophenotypic factors. Our findings indicate a strong correlation between PGP expression in myeloma and past chemotherapy in myeloma, in particular, related to prior exposure to the natural product agents vincristine and doxorubicin. Additionally, the proportion of PGP- positive plasma cells was significantly higher in the doxorubicin- treated patients than the nondoxorubicin-treated patients (87.7% v 65.17%; P = .013). Combined high vincristine and doxorubicin total dosage appear highly predictive of PGP expression.

scholarly journals P-glycoprotein expression and function in circulating blood cells from normal volunteers

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2451-2458 ◽  
Author(s):  
WT Klimecki ◽  
BW Futscher ◽  
TM Grogan ◽  
WS Dalton
Keyword(s):  
Nk Cell ◽  
Efflux Pump ◽  
Immunoblot Analysis ◽  
Rhodamine 123 ◽  
Double Labeling ◽  
Normal Volunteers ◽  
P Glycoprotein ◽  
Mdr1 Mrna ◽  
Mrna Analysis ◽  
And Function

Abstract In contrast to its clearly defined role as a multidrug efflux pump in neoplastic cells, the physiologic function of P-glycoprotein (P-gly) in normal cells is unclear. Recent reports identifying P-gly in normal blood and bone marrow suggest that hematopoietic development or function may be dependent on P-gly. To understand the normal function of P-gly in the blood, its level of expression and function must first be quantitated relative to a known standard. In this study, P-gly, MDR1 gene expression, and P-gly function were quantitated in normal leukocytes. P-gly and MDR1 expression were analyzed in individual leukocyte lineages (T-helper, T-suppressor, monocyte, granulocyte, B- lymphocyte, NK cell) from normal volunteers. P-gly on the cell surface was detected by fluorescent double-labeling for lineage (CD4, CD8, CD14, CD15, CD19, CD56, respectively) and P-gly (MRK16) with analysis by flow cytometry and in some cases immunoblot analysis. MDR1 mRNA analysis on purified lineages was performed using quantitative reverse transcription-polymerase chain reaction. P-gly function was determined for each lineage using dual-labeling for lineage and P-gly substrate (rhodamine 123). The P-gly expressing human myeloma cell line, 8226/Dox6, was used as a reference of comparison for levels of P-gly, MDR1 mRNA, and function. CD56+ cells expressed the highest levels of MDR1 mRNA followed by CD8+ > CD4+ approximately equal to CD15+ > CD19+ > CD14+, with percentage values relative to Dox6 of 49%, 17%, 8%, 8%, 4%, and 2%, respectively. The assays for P-gly immunofluorescence and function correlated well with mRNA analysis except for CD15+ cells (granulocytes), which showed a moderate MDR1 mRNA level with a lack of both function and surface P-gly staining. Granulocyte membranes did show P-gly on immunoblot analysis when probed with either C219 or JSB1. We conclude that (1) P-gly and the MDR1 mRNA are expressed in normal leukocytes, (2) this P-gly expression is lineage specific with relatively high levels among CD56+ cells, and (3) the expression of P- gly in granulocytes is not associated with transport of the P-gly substrate, rhodamine 123, out of the cell.

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