scholarly journals Copper affect the multixenobiotic resistance mechanism (MXR) in embryo and larvae of Rhamdia quelen

2021 ◽  
Vol 16 (1) ◽  
pp. 63-68
Author(s):  
Oliveira Ribeiro C.A. ◽  
Azevedo A.C.B. ◽  
Bombardelli R.A. ◽  
Randi M.A.F.
Keyword(s):  
Abc Transporters ◽  
Resistance Mechanism ◽  
Aquatic Organisms ◽  
Inhibitory Effect ◽  
Multidrug Resistance Protein ◽  
Multixenobiotic Resistance ◽  
Adult Females ◽  
Atp Binding Cassette Transporters ◽  
Rhamdia Quelen ◽  
Resistance Protein

P-glycoproteins (P-gp) and Multidrug resistance protein (MRP) represent a family of ABC (ATP-binding cassette) transporters responsible for multixenobiotic resistance mechanism (MXR) in aquatic organisms. In the current study the modulation of P-gp and MRP proteins was evaluated in embryo and larvae of Rhamdia quelen fish species exposed to copper. Adult females were exposed by gavage during 60 days to copper (5 mg Cu kg-1) and eggs, embryos, and larvae from exposed and unexposed females were exposed to 30 mg Cu L-1. The activity of ABC transporters was accessed via calcein accumulation assay using the specific inhibitors: Verapamil (P-gp) and MK571 (MRP). P-gp activity was detected in all analyzed stages whereas MRP activity was observed after 36 and 96 hpf. Oocytes from females previously exposed and larvae stages (36 and 96 hpf) accumulated less calcein than no exposed oocytes, showing higher ABC transporters activity. In individuals exposed to copper, a higher inhibitory effect was observed 1 hpf. The modulation of ABC transporter proteins is time dependent throughout the development, and the initial stages are more sensible to copper. These findings highlight the MXR mechanism as a biomarker of pollutant exposure in early stages of development of R. quelen.

Inhibition of multixenobiotic resistance mechanism in aquatic organisms by commercially used pesticides

2000 ◽  
Vol 50 (1-5) ◽  
pp. 334-335 ◽  
Author(s):  
T. Smital ◽  
R. Sauerborn ◽  
B. Pivčević ◽  
B. Kurelec
Keyword(s):  
Resistance Mechanism ◽  
Aquatic Organisms ◽  
Multixenobiotic Resistance

scholarly journals A Computational Approach towards the Understanding of Plasmodium falciparum Multidrug Resistance Protein 1

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Saumya K. Patel ◽  
Linz-Buoy George ◽  
Sivakumar Prasanth Kumar ◽  
Hyacinth N. Highland ◽  
Yogesh T. Jasrai ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Resistance Mechanism ◽  
Structural Motif ◽  
Multidrug Resistance Protein ◽  
Mutant Type ◽  
Multidrug Resistance Protein 1 ◽  
Antimalarial Resistance ◽  
Resistant Strains ◽  
Resistance Protein

The emergence of drug resistance in Plasmodium falciparum tremendously affected the chemotherapy worldwide while the intense distribution of chloroquine-resistant strains in most of the endemic areas added more complications in the treatment of malaria. The situation has even worsened by the lack of molecular mechanism to understand the resistance conferred by Plasmodia species. Recent studies have suggested the association of antimalarial resistance with P. falciparum multidrug resistance protein 1 (PfMDR1), an ATP-binding cassette (ABC) transporter and a homologue of human P-glycoprotein 1 (P-gp1). The present study deals about the development of PfMDR1 computational model and the model of substrate transport across PfMDR1 with insights derived from conformations relative to inward- and outward-facing topologies that switch on/off the transportation system. Comparison of ATP docked positions and its structural motif binding properties were found to be similar among other ATPases, and thereby contributes to NBD domains dimerization, a unique structural agreement noticed in Mus musculus Pgp and Escherichia coli MDR transporter homolog (MsbA). The interaction of leading antimalarials and phytochemicals within the active pocket of both wild-type and mutant-type PfMDR1 demonstrated the mode of binding and provided insights of less binding affinity thereby contributing to parasite’s resistance mechanism.

Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues

2002 ◽  
Vol 361 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Liqi LAI ◽  
Theresa M. C. TAN
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Transmembrane Domain ◽  
The Other ◽  
Nucleoside Analogues ◽  
Intracellular Camp ◽  
Multidrug Resistance Protein ◽  
Purine Analogues ◽  
Resistance Protein

Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4, ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD0, which is present in the other MRPs. Using cells stably overexpressing ABCC4, this study shows that ABCC4 exports GSH. ABCC4 also facilitates the efflux of cAMP. Depletion of intracellular GSH with dl-buthionine-(S,R)-sulphoximine led to decreased export of cAMP and a corresponding increase in intracellular cAMP was observed. ABCC4 also mediates resistance to purine analogues 9-(2-phosphonylmethoxyethyl)-adenine and 6-thioguanine. This resistance can be reversed by the presence of dl-buthionine-(S,R)-sulphoximine. We conclude that as well as nucleotide and nucleoside analogues, ABCC4 can mediate the export of GSH. In addition, GSH plays an important role in the function of ABCC4. Depletion of intracellular GSH adversely affects the export of cAMP by ABCC4. Resistance to nucleoside analogues is also adversely affected by depletion of cellular GSH.

scholarly journals The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

2020 ◽  
Vol 21 (7) ◽  
pp. 2630
Author(s):  
Francisco V.C. Mello ◽  
Gabriela N. de Moraes ◽  
Raquel C. Maia ◽  
Jennifer Kyeremateng ◽  
Surtaj Hussain Iram ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Graphene Quantum Dots ◽  
Atp Binding ◽  
Multidrug Resistance Protein ◽  
Membrane Expression ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Atp Binding Cassette

The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs. Among the mechanisms involved in the multidrug resistance, the participation of ATP-binding cassette (ABC) transporters is the main one. The ABC transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, which are expressed in cancer. They are involved in the clearance of intracellular metabolites as ions, hormones, lipids and other small molecules from the cell, affecting directly and indirectly drug absorption, distribution, metabolism and excretion. Other mechanisms responsible for resistance are the signaling pathways and the anti- and pro-apoptotic proteins involved in cell death by apoptosis. In this study we evaluated the influence of three nanosystem (Graphene Quantum Dots (GQDs), mesoporous silica (MSN) and poly-lactic nanoparticles (PLA)) in the main mechanism related to the cancer multidrug resistance such as the Multidrug Resistance Protein-1 and P-glycoprotein. We also evaluated this influence in a group of proteins involved in the apoptosis-related resistance including cIAP-1, XIAP, Bcl-2, BAK and Survivin proteins. Last, colonogenic and MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assays have also been performed. The results showed, regardless of the concentration used, GQDs, MSN and PLA were not cytotoxic to MDA-MB-231 cells and showed no impairment in the colony formation capacity. In addition, it has been observed that P-gp membrane expression was not significantly altered by any of the three nanomaterials. The results suggest that GQDs nanoparticles would be suitable for the delivery of other multidrug resistance protein 1 (MRP1) substrate drugs that bind to the transporter at the same binding pocket, while MSN can strongly inhibit doxorubicin efflux by MRP1. On the other hand, PLA showed moderate inhibition of doxorubicin efflux by MRP1 suggesting that this nanomaterial can also be useful to treat MDR (Multidrug resistance) due to MRP1 overexpression.

scholarly journals Impact of Multidrug Resistance Protein-4 Inhibitors on Modulating Platelet Function and High on-Aspirin Treatment Platelet Reactivity

2018 ◽  
Vol 118 (03) ◽  
pp. 490-501 ◽  
Author(s):  
Laura Alemanno ◽  
Isabella Massimi ◽  
Vanessa Klaus ◽  
Maria Guarino ◽  
Teresa Maltese ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
Multidrug Resistance Protein ◽  
Resistance Protein ◽  
The Impact

AbstractPlatelet multidrug resistance protein 4 (MRP4) plays a modulating role on platelet activation. Platelet function and thrombus formation are impaired in MRP4 knockout mice models, and, among aspirin-treated patients, high on-aspirin residual platelet reactivity (HARPR) positively correlates with MRP4 levels. To better understand the effects of MRP4 on platelet function, the aim of this investigation was to assess the impact of cilostazol-induced inhibition of MRP4-mediated transport and assess aspirin-induced antiplatelet effects and rates of HARPR in human subjects.Cilostazol-dependent inhibition of MRP4-mediated transport was assessed with the release of the fluorescent adduct bimane-glutathione and aspirin entrapment. Effect of Cilostazol on cAMP inhibition was evaluated by vasodilator-stimulated phosphoprotein (VASP). Platelet function was studied by collagen and TRAP-6-induced platelet aggregation and secretion.Cilostazol reduced the release of bimane-glutathione and enhanced aspirin entrapment demonstrating an inhibitory effect on MRP4 in platelets. VASP phosphorylation was absent until 10 seconds after addition of cilostazol, and becomes evident after 30 seconds. An inhibitory effect on platelet aggregation and secretion was found in activated platelets, with threshold concentration of agonists, 10 seconds after addition of cilostazol, supporting a role of MRP4 on platelet function that is cAMP independent. Cilostazol effects were also shown in aspirin-treated platelets. A reduction of platelet aggregation and secretion were observed in aspirin-treated patients with HARPR.This study supports the role of MRP4 on modulating platelet function which occurs through cAMP-independent mechanisms. Moreover, inhibition of MRP4 induced by cilostazol enhances aspirin-induced antiplatelet effects and reduces HARPR.

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