A critical review on modulators of Multidrug Resistance Protein 1 in cancer cells

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent efflux transporter, and responsible for the transport of a broad spectrum of xenobiotics, toxins, and physiological substrates across the plasma membrane. As an efflux pump, it plays a significant role in the absorption and disposition of drugs including anticancer drugs, antivirals, antimalarials, and antibiotics and their metabolites across physiological barriers in cells. MRP1 is also known to aid in the regulation of several physiological processes such as redox homeostasis, steroid metabolism, and tissue defense. However, its overexpression has been reported to be a key clinical marker associated with multidrug resistance (MDR) of several types of cancers including lung cancer, childhood neuroblastoma, breast and prostate carcinomas, often resulting in a higher risk of treatment failure and shortened survival rates in cancer patients. Aside MDR, overexpression of MRP1 is also implicated in the development of neurodegenerative and cardiovascular diseases. Due to the cellular importance of MRP1, the identification and biochemical/molecular characterization of modulators of MRP1 activity and expression levels are of key interest to cancer research and beyond. This review primarily aims at highlighting the physiological and pharmacological importance of MRP1, known MRP1 modulators, current challenges encountered, and the potential benefits of conducting further research on the MRP1 transporter.

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

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.

The First Cytoplasmic Loop in the Core Structure of the ABCC1 (Multidrug Resistance Protein 1; MRP1) Transporter Contains Multiple Amino Acids Essential for Its Expression

ABCC1 (human multidrug resistance protein 1 (hMRP1)) is an ATP-binding cassette transporter which effluxes xeno- and endobiotic organic anions and confers multidrug resistance through active drug efflux. The 17 transmembrane α-helices of hMRP1 are distributed among three membrane spanning domains (MSD0, 1, 2) with MSD1,2 each followed by a nucleotide binding domain to form the 4-domain core structure. Eight conserved residues in the first cytoplasmic loop (CL4) of MSD1 in the descending α-helix (Gly392, Tyr404, Arg405), the perpendicular coupling helix (Asn412, Arg415, Lys416), and the ascending α-helix (Glu422, Phe434) were targeted for mutagenesis. Mutants with both alanine and same charge substitutions of the coupling helix residues were expressed in HEK cells at wild-type hMRP1 levels and their transport activity was only moderately compromised. In contrast, mutants of the flanking amino acids (G392I, Y404A, R405A/K, E422A/D, and F434Y) were very poorly expressed although Y404F, E422D, and F434A were readily expressed and transport competent. Modeling analyses indicated that Glu422 and Arg615 could form an ion pair that might stabilize transporter expression. However, this was not supported by exchange mutations E422R/R615E which failed to improve hMRP1 levels. Additional structures accompanied by rigorous biochemical validations are needed to better understand the bonding interactions crucial for stable hMRP1 expression.

Multidrug Resistance Protein 4 (MRP4/ABCC4): A Suspected Efflux Transporter for Human’s Platelet Activation

: The main role of platelets is to contribute to hemostasis. However, under pathophysiological conditions, platelet activation may lead to thrombotic events of cardiovascular diseases. Thus, anti-thrombotic treatment is important in patients with cardiovascular disease. This review focuses on a platelet receptor, a transmembrane protein, the Multidrug Resistance Protein 4, MRP4, which contributes to platelet activation by extruding endogenous molecules responsible for their activation and accumulation. The regulation of the intracellular concentration levels of these molecules by MRP4 turned to make the protein suspicious and, at the same time, an interesting regulatory factor of normal platelet function. Especially, the possible role of MRP4 in the excretion of xenobiotic and antiplatelet drugs such as aspirin is discussed, thus imparting platelet aspirin tolerance and correlating the protein with the ineffectiveness of aspirin antiplatelet therapy. Based on the above, this review finally underlines that the development of a highly selective and targeted strategy for platelet MRP4 inhibition will also lead to inhibition of platelet activation and accumulation.

Changes in Gene Expression Profiling and Phenotype in Aged Multidrug Resistance Protein 4-Deficient Mouse Retinas

Multidrug resistance protein 4 (MRP4) is an energy-dependent membrane transporter responsible for cellular efflux of a broad range of xenobiotics and physiological substrates. In this trial, we aimed to investigate the coeffects of aging and MRP4 deficiency using gene expression microarray and morphological and electrophysiological analyses of mouse retinas. Mrp4-knockout (null) mice and wild-type (WT) mice were reared in the same conditions to 8–12 weeks (young) or 45–55 weeks (aged). Microarray analysis identified 186 differently expressed genes from the retinas of aged Mrp4-null mice as compared to aged WT mice, and subsequent gene ontology and KEGG pathway analyses showed that differently expressed genes were related to lens, eye development, vision and transcellular barrier functions that are involved in metabolic pathways or viral infection pathways. No significant change in thickness was observed for each retinal layer among young/aged WT mice and young/aged Mrp4-null mice. Moreover, immunohistochemical analyses of retinal cell type did not exhibit an overt change in the cellular morphology or distribution among the four age/genotype groups, and the electroretinogram responses showed no significant differences in the amplitude or the latency between aged WT mice and aged Mrp4-null mice. Aging would be an insufficient stress to cause some damage to the retina in the presence of MRP4 deficiency.