scholarly journals Expressional Study of Permeability glycoprotein (P-gp) and Multidrug Resistance Protein 1 (MRP-1) in Drug-Resistant Mesial Temporal Lobe Epilepsy

2021 ◽  
pp. 1-31
Author(s):  
Mandeep Kaur ◽  
◽  
Tulika Gupta ◽  
Mili Gupta ◽  
Parampreet S. Kharbanda ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Mesial Temporal Lobe Epilepsy ◽  
Efflux Transporters ◽  
P Value ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Glycoprotein P ◽  
Mesial Temporal Lobe ◽  
Drug Efflux Transporters

About 30% of epileptic patients do not react to anti-epileptic drugs leading to refractory seizures. The pathogenesis of drug-resistance in Mesial Temporal Lobe Epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1). The major drawback so far is the expressional analysis of transporters in equal numbers of drug-resistant epileptic tissue and age-matched non-epileptic tissue. We have studied these two transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery (n=15) and compared their expression profile with the tissues resected from non-epileptic autopsy cases (n=15). Statistically significant over expression of both P-gp (p-value <0.0001) and MRP-1 (p-value 0.01) at gene and protein levels was found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of patient group showed increased immunoreactivity of P-gp at blood brain barrier and increased reactivity of MRP-1 in parenchyma. The results were confirmed by confocal immunofluorescence microscopy. The study demonstrated that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy

scholarly journals Role of Permeability glycoprotein (P-gp) and Multidrug resistance protein 1 (MRP-1) in drug-resistance in mesial temporal lobe epilepsy

2021 ◽  
Author(s):  
Mandeep Kaur ◽  
Tulika Gupta ◽  
Mili Gupta ◽  
Navneet Singla ◽  
Parampreet Singh ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mesial Temporal Lobe Epilepsy ◽  
Efflux Transporters ◽  
P Value ◽  
Drug Efflux ◽  
Multidrug Resistance Protein ◽  
Glycoprotein P ◽  
Multidrug Resistance Protein 1 ◽  
Resistance Protein ◽  
Mesial Temporal Lobe

About 30% of patients with epilepsy do not respond to anti-epileptic drugs leading to refractory seizures. The pathogenesis of drug-resistance in Mesial Temporal Lobe Epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance protein-1 (MRP-1). We have studied these two transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery and compared their expression profile with the tissues resected from non-epileptic autopsy cases. Statistically significant over expression of both P-gp (p-value<0.0001) and MRP-1 (p-value 0.01) at gene and protein levels was found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of patient group showed increased immunoreactivity of P-gp at blood brain barrier and increased reactivity of MRP-1 in parenchyma. The results were confirmed by confocal immunofluorescence microscopy. This suggested that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy.

Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade

2016 ◽  
Vol 370 (1) ◽  
pp. 153-164 ◽  
Author(s):  
Zhaolin Chen ◽  
Tianlu Shi ◽  
Lei Zhang ◽  
Pengli Zhu ◽  
Mingying Deng ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Efflux Transporters ◽  
Atp Binding ◽  
Drug Efflux ◽  
The Past ◽  
Drug Efflux Transporters ◽  
Atp Binding Cassette

scholarly journals Drug Efflux Transporters Are Overexpressed in Short-Term Tamoxifen-Induced MCF7 Breast Cancer Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Desak Gede Budi Krisnamurti ◽  
Melva Louisa ◽  
Erlia Anggraeni ◽  
Septelia Inawati Wanandi
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Short Period ◽  
Drug Efflux Transporters

Tamoxifen is the first line drug used in the treatment of estrogen receptor-positive (ER+) breast cancer. The development of multidrug resistance (MDR) to tamoxifen remains a major challenge in the treatment of cancer. One of the mechanisms related to MDR is decrease of drug influx via overexpression of drug efflux transporters such as P-glycoprotein (P-gp/MDR1), multidrug resistance associated protein (MRP), or BCRP (breast cancer resistance protein). We aimed to investigate whether the sensitivity of tamoxifen to the cells is maintained through the short period and whether the expressions of several drug efflux transporters have been upregulated. We exposed MCF7 breast cancer cells with tamoxifen 1 μM for 10 passages (MCF7 (T)). The result showed that MCF7 began to lose their sensitivity to tamoxifen from the second passage. MCF7 (T) also showed a significant increase in all transporters examined compared with MCF7 parent cells. The result also showed a significant increase of CC50 in MCF7 (T) compared to that in MCF7 (97.54 μM and 3.04 μM, resp.). In conclusion, we suggest that the expression of several drug efflux transporters such as P-glycoprotein, MRP2, and BCRP might be used and further studied as a marker in the development of tamoxifen resistance.

scholarly journals Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

2016 ◽  
Vol 60 (9) ◽  
pp. 5563-5572 ◽  
Author(s):  
Martina Ceckova ◽  
Josef Reznicek ◽  
Zuzana Ptackova ◽  
Lukas Cerveny ◽  
Fabian Müller ◽  
...  
Keyword(s):  
Mdck Cells ◽  
Antiretroviral Drugs ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Glycoprotein P ◽  
Term Placenta ◽  
Placental Transport ◽  
Hiv Positive Women ◽  
Drug Efflux Transporters

ABSTRACTLamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employedin vitroaccumulation and transport experiments on MDCK cells overexpressing drug efflux transporters,in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparentKmof 4.21 mM andVmaxof 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent within vitrotransport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

scholarly journals Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

2015 ◽  
Vol 59 (5) ◽  
pp. 2572-2582 ◽  
Author(s):  
M. Tozammel Hoque ◽  
Olena Kis ◽  
María F. De Rosa ◽  
Reina Bendayan
Keyword(s):  
Human Blood ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Concurrent Administration ◽  
Glycoprotein P ◽  
Blood Brain ◽  
Drug Efflux Transporters

ABSTRACTThe objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluatedin vitroin (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using anin situsingle-pass intestinal perfusion model. [3H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [3H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [3H]raltegravir efflux ratios. In rat intestinal segments, [3H]raltegravirin situpermeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 μM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([3H]mitoxantrone), or MRP1 [2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK-ABCG2-, or HeLa-MRP1-overexpressing cells, respectively. Our data suggest that raltegravir is a substrate but not an inhibitor of the drug efflux transporters P-gp and BCRP. These transporters might play a role in the restriction of raltegravir permeability across the blood-brain, blood-testicular, and blood-intestinal barriers, potentially contributing to its low tissue concentrations and/or low oral bioavailability observed in the clinic setting.

scholarly journals P-glycoprotein Mediated Efflux Modulators of Plant Origin: A Short Review

2016 ◽  
Vol 11 (5) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Nuno Silva ◽  
Lígia Salgueiro ◽  
Ana Fortuna ◽  
Carlos Cavaleiro
Keyword(s):  
Short Review ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Plant Origin ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Plant Compounds ◽  
Drug Efflux Transporters

Drug efflux transporters such as P-glycoprotein (P-gp) help maintain cellular homeostasis but are also major contributors to the development of multidrug resistance (MDR) phenomena. Since P-gp was associated with MDR, several compounds showing potential to inhibit this transporter have been identified. Particular attention has been given to natural products, namely those of plant origin, looking for highly effective and safe P-gp inhibitors with little to no interaction with other cellular or metabolic processes. Here we abridge several examples of plant compounds from distinct classes, polyketides, lignans, anthraquinones, coumarins, alkaloids, mono- and sesqui-terpenes, steroids and limonoids, which have shown the ability to modulate in vitro or in vivo the P-gp activity.

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