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Journal articles on the topic 'MRP4 (Multidrug Resistance Associated Protein 4)'

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Published: 8 June 2023

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1

Steinbach, Daniel, Susann Wittig, Gunnar Cario, Susanne Viehmann, Angelika Mueller, Bernd Gruhn, Ralf Haefer, Felix Zintl, and Axel Sauerbrey. "The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype." Blood 102, no. 13 (December 15, 2003): 4493–98. http://dx.doi.org/10.1182/blood-2002-11-3461.

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Abstract The family of multidrug resistance-associated proteins (MRPs) belongs to the superfamily of adenosine triphosphate-binding-cassette (ABC) transporters, which have the ability to function as outward pumps for chemotherapeutic drugs and therefore might be involved in drug resistance. In this study the expression of the MRP2, MRP3, MRP4, MRP5, and SMRP genes was measured using TaqMan real-time polymerase chain reaction (PCR) in 103 children with previously untreated acute lymphoblastic leukemia (ALL) (precursor B-cell ALL [B-ALL], n = 71; T-cell ALL [T-ALL], n = 32). All 5 genes were expressed with a great variability. Only MRP3 expression was associated with a significantly worse prognosis (P = .008). The median expression of MRP3 was 10-fold higher in T-ALL than in precursor B-ALL (P < .001) and 4-fold higher in male patients than in female patients (P < .001). The prognostic impact of MRP3 was independent of immunophenotype or sex. Higher levels of MRP3 were found in patients with a poor in vivo response to prednisone, but this could not be confirmed in an independent case-control study (40 patients) for prednisone response. In healthy donors, the median expression of MRP4 was 4-fold higher in bone marrow and 8-fold higher in CD34+ stem cells compared with peripheral blood (P = .002). Our results suggest that MRP3 is involved in drug resistance in childhood ALL. It therefore represents an interesting target to overcome multidrug resistance. High levels of MRP3 could possibly be the reason for the poorer prognosis of male patients or patients who have T-ALL. Similar to other members of the family of ABC transporters, MRP4 seems to be a marker for immature stem cells. (Blood. 2003;102:4493-4498)

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2

Ansari, Marc, Geraldine Sauty, Albert Moghrabi, and Maja Krajinovic. "Polymorphisms in Multidrug Resistance-Associated Protein Genes Are Associated with Worse Outcome in Childhood Acute Lymphoblastic Leukemia." Blood 110, no. 11 (November 16, 2007): 1443. http://dx.doi.org/10.1182/blood.v110.11.1443.1443.

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Abstract Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of childhood acute lymphoblastic leukemia (ALL). Inter-individual differences in response to this drug may cause treatment failures and adverse drug reactions. In particular, transporters of the adenosine triphosphate-binding cassette (ABC) family such as the ABCC (multidrug resistance-related protein, MRP) are involved in the efflux of this drug. The elimination of MTX may arise, among other factors, to be a major determinant of chemoresistance in leukemic blast cells. It has been demonstrated that ALL patients with high MRP expression had an unfavourable prognosis with relapsed patients showing a higher expression of MRP genes. The polymorphisms in MRP genes, particularly those in promoter region may explain differences in expression and thereby the inter-individual differences in clinical outcome for ALL children. We analyzed polymorphisms in five MRP genes (MRP1-MRP5). Two polymorphisms in MRP1, 7 in MRP2, 4 in MRP3, 8 in MRP4 and 3 in MRP5 gene, located in regulatory and coding gene regions were selected from NCBI dbSNP database. The polymorphisms were analyzed in 50 healthy individuals to estimate allele frequency, linkage disequilibrium, and haplotype phase. Variants sufficient to infer most common haplotypes were further analyzed in 243 children with de novo ALL, treated at Ste-Justine Hospital with multi-agent chemotherapy according to the Dana-Farber Cancer Institute protocols 87-01, 91-01, 95-01 and 2000-01. These polymorphisms/haplotypes were investigated for association with disease outcome. The polymorphisms of two genes, MRP1 and MRP3, appeared associated with event free survival (EFS). Individuals with the AA -genotype of A -1665G promoter polymorphism in MRP1 gene had worse EFS (69% vs. 85%, p=0.007) compared to patients with the GG or AG genotypes (Hazard ratio, HR=2.2 (IC 95%: 1.2–3.9). Carriers of A allele of G-1696A and A-189T polymorphisms in the MRP3 gene had a worse EFS (68% vs. 81%, p=0.016) compared to those with the GG or TT genotype respectively (HR=2,1 IC 95%: 1.1–3.8). The A alleles of both polymorphisms belong to the same haplotype. A-189 is uniquely tagging this haplotype, therefore the association between this haplotype and ALL outcome was also found. A-1696 is shared among this and additional haplotype, the latter not associated with EFS, rendering A-1696 allele less relevant for the prediction of ALL outcome. All associations remained significant in multivariate analysis after inclusion of the known prognostic factors. Similar results were obtained if disease free and overall survival were analyzed instead of EFS. As MRPs are also expressed in the blood-brain barrier, a possible correlation between these polymorphisms and type of relapse (isolated bone marrow or central nervous system) was analysed. No significant difference between the type of relapse and MRP1 or MRP3 described polymorphisms was seen. The variants MRP1 A-1665, and MRP3 A-189 localised in the regulatory region of these genes, have an impact on the outcome in ALL children and could predict differences in MTX response. Further analysis between these polymorphisms and MTX levels as well as combined effect with other at risk genotypes of the folate cycle should be analysed to determine the effect of MRP variants on the outcome of children with ALL.

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3

Donepudi, Ajay C., Gregory J. Smith, Oladimeji Aladelokun, Yoojin Lee, Steven J. Toro, Marisa Pfohl, Angela L. Slitt, et al. "Lack of Multidrug Resistance-associated Protein 4 Prolongs Partial Hepatectomy-induced Hepatic Steatosis." Toxicological Sciences 175, no. 2 (April 24, 2020): 301–11. http://dx.doi.org/10.1093/toxsci/kfaa032.

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Abstract Multidrug resistance-associated protein 4 (Mrp4) is an efflux transporter involved in the active transport of several endogenous and exogenous chemicals. Previously, we have shown that hepatic Mrp4 expression increases following acetaminophen overdose. In mice, these increases in Mrp4 expression are observed specifically in hepatocytes undergoing active proliferation. From this, we hypothesized that Mrp4 plays a key role in hepatocyte proliferation and that lack of Mrp4 impedes liver regeneration following liver injury and/or tissue loss. To evaluate the role of Mrp4 in these processes, we employed two-third partial hepatectomy (PH) as an experimental liver regeneration model. In this study, we performed PH-surgery on male wildtype (C57BL/6J) and Mrp4 knockout mice. Plasma and liver tissues were collected at 24, 48, and 72 h postsurgery and evaluated for liver injury and liver regeneration endpoints, and for PH-induced hepatic lipid accumulation. Our results show that lack of Mrp4 did not alter hepatocyte proliferation and liver injury following PH as evaluated by Ki-67 antigen staining and plasma alanine aminotransferase levels. To our surprise, Mrp4 knockout mice exhibited increased hepatic lipid content, in particular, di- and triglyceride levels. Gene expression analysis showed that lack of Mrp4 upregulated hepatic lipin1 and diacylglycerol O-acyltransferase 1 and 2 gene expression, which are involved in the synthesis of di- and triglycerides. Our observations indicate that lack of Mrp4 prolonged PH-induced hepatic steatosis in mice and suggest that Mrp4 may be a novel genetic factor in the development of hepatic steatosis.

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4

Horvah, L. G., L. Ho, J. G. Kench, J. A. Allen, G. L. Scheffer, P. D. Stricker, J. J. Grygiel, R. L. Sutherland, and S. M. Henshall. "Elevated multidrug resistance-associated protein 4 (MRP4) expression in localized prostate cancer—A potential androgen regulated protein." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 20022. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.20022.

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20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump which transports prostaglandins, nucleoside analogues, glutamate and phosphate analogues. High MRP4 expression is prognostic of poor outcome in neuroblastoma and also correlates with MYCN amplification, suggesting regulation by this oncogene. Although MRP4 is known to be expressed in normal prostate epithelium, its expression in prostate cancer (PC) is undefined. This study aimed to define the pattern of expression of MRP4 in normal and malignant prostate tissue and assess the association with androgen exposure. Methods: 84 radical prostatectomy specimens from patients with clinically localized PC (22 neoadjuvant androgen ablation therapy, 62 no neoadjuvant treatment), 42 specimens of hyperplasia adjacent to PC and 16 cases of advanced PC were assessed for MRP4 expression using in situ hybridisation and immunohistochemistry. PC cell lines were assessed by immunoblotting. Results: There were significantly higher levels of MRP4 mRNA and protein expression in localized PC compared to hyperplasia (p=0.006). Conversely, MRP4 protein levels were significantly decreased in PCs treated with neoadjuvant androgen ablation therapy compared to cancers exposed to normal testosterone levels (p < 0.0001). There was also a trend towards decreased MRP4 expression in advanced PCs. Furthermore, immunoblotting revealed that MRP4 protein was more highly expressed in androgen-dependent (LNCaP) compared to androgen-independent (PC3/DU145) cell lines. In addition, in a panel of 14 normal human tissues only kidney and prostate tissue expressed MRP4 protein suggesting limited expression of MRP4 in human tissues. Discussion: Elevated MRP4 expression is found in malignant compared to benign prostate tissue while lower MRP4 expression is seen after androgen ablation suggesting that MRP4 may be an androgen-regulated gene. In addition, there is relatively little expression of MRP4 in normal tissues. These data suggest that MRP4 is important in the progression to PC and that it may be a potential therapeutic target. No significant financial relationships to disclose.

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5

Zhang, Jing, Ka-Yun Ng, and Paul C. Ho. "Interaction of Oxazaphosphorines with Multidrug Resistance-Associated Protein 4 (MRP4)." AAPS Journal 12, no. 3 (April 20, 2010): 300–308. http://dx.doi.org/10.1208/s12248-010-9189-x.

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6

Hardwick, Rhiannon N., Marina Snellings, Brian C. Ferslew, Yang Lu, and Kim L. R. Browuer. "Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)." ADMET and DMPK 4, no. 4 (December 26, 2016): 302. http://dx.doi.org/10.5599/admet.4.4.322.

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<p class="PaperKeywordTitle">Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI) and aurora (AKI) kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC) transporters such as P-glycoprotein and breast cancer resistance protein (BCRP), which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs), remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC<sub>50 </sub>values were estimated by determining TKI/AKI inhibition of MRP4-mediated [<sup>3</sup>H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [<sup>3</sup>H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (C<sub>ss</sub>) to the IC<sub>50</sub> for each compound was calculated with C<sub>ss</sub>/IC<sub>50</sub> ratio >0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of BCRP was much more extensive and included alisertib, barasertib, danusertib, enzastaurin, erlotinib, gefitinib, imatinib, neratinib, nilotinib, pazopanib, selumetinib, sorafenib, sunitinib, tozasertib, and vandetanib. These findings indicate the significant potential for TKI/AKIs to inhibit multiple ABC efflux transporters. The resulting inhibition data could provide insight regarding the clinical interpretation of pharmacokinetic/pharmacodynamic outcomes when TKI/AKIs are administered concomitantly with additional chemotherapeutic agents.</p>

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7

Hayashi, Hisamitsu, Sotaro Naoi, Takayuki Nakagawa, Toru Nishikawa, Hiroyuki Fukuda, Shinobu Imajoh-Ohmi, Ayano Kondo, et al. "Sorting Nexin 27 Interacts with Multidrug Resistance-associated Protein 4 (MRP4) and Mediates Internalization of MRP4." Journal of Biological Chemistry 287, no. 18 (March 12, 2012): 15054–65. http://dx.doi.org/10.1074/jbc.m111.337931.

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8

Ansari, Marc, Géraldine Sauty, Malgorzata Labuda, Vincent Gagné, Caroline Laverdière, Albert Moghrabi, Daniel Sinnett, and Maja Krajinovic. "Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia." Blood 114, no. 7 (August 13, 2009): 1383–86. http://dx.doi.org/10.1182/blood-2008-11-191098.

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Abstract Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P = .02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.

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9

May, M., C. Alejandro, N. Gomez, F. Diez, S. Copsel, J. Iturbe, N. Mohr, N. Fernandez, C. Shayo, and C. Davio. "P-020 Targeting multidrug resistance – associated protein 4 (MRP4/ABCC4) in pancreatic cancer." Annals of Oncology 27 (June 2016): ii6. http://dx.doi.org/10.1093/annonc/mdw199.20.

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10

Sassi, Y., S. El Haou, Y. Fromes, N. Mougenot, G. Vandecasteel, P. Lechat, S. Hatem, A. M. Lompre, and J. S. Hulot. "J016 Inhibition of the multidrug resistance-associated protein 4, MRP4 promotes cardiac hypertrophy." Archives of Cardiovascular Diseases 102 (March 2009): S108. http://dx.doi.org/10.1016/s1875-2136(09)72391-5.

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11

Marzolini, C. "Identification of single nucleotide polymorphisms in the multidrug resistance-associated protein 4 (MRP4)." Clinical Pharmacology & Therapeutics 75, no. 2 (February 2004): P93. http://dx.doi.org/10.1016/j.clpt.2003.11.354.

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12

Ho, Lye Lin, James G. Kench, David J. Handelsman, George L. Scheffer, Phillip D. Stricker, John G. Grygiel, Robert L. Sutherland, Susan M. Henshall, John D. Allen, and Lisa G. Horvath. "Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer." Prostate 68, no. 13 (September 15, 2008): 1421–29. http://dx.doi.org/10.1002/pros.20809.

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13

Campion, Sarah N., Rachel Johnson, Lauren M. Aleksunes, Michael J. Goedken, Nico van Rooijen, George L. Scheffer, Nathan J. Cherrington, and José E. Manautou. "Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function." American Journal of Physiology-Gastrointestinal and Liver Physiology 295, no. 2 (August 2008): G294—G304. http://dx.doi.org/10.1152/ajpgi.00541.2007.

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During acetaminophen (APAP) hepatotoxicity, increased expression of multidrug resistance-associated proteins 2, 3, and 4 (Mrp2-4) occurs. Mrp4 is the most significantly upregulated transporter in mouse liver following APAP treatment. Although the expression profiles of liver transporters following APAP hepatotoxicity are well characterized, the regulatory mechanisms contributing to these changes remain unknown. We hypothesized that Kupffer cell-derived mediators participate in the regulation of hepatic transporters during APAP toxicity. To investigate this, C57BL/6J mice were pretreated with clodronate liposomes (0.1 ml iv) to deplete Kupffer cells and then challenged with APAP (500 mg/kg ip). Liver injury was assessed by plasma alanine aminotransferase and hepatic transporter protein expression was determined by Western blot and immunohistochemistry. Depletion of Kupffer cells by liposomal clodronate increased susceptibility to APAP hepatotoxicity. Although increased expression of several efflux transporters was observed after APAP exposure, only Mrp4 was found to be differentially regulated following Kupffer cell depletion. At 48 and 72 h after APAP dosing, Mrp4 levels were increased by 10- and 33-fold, respectively, in mice receiving empty liposomes. Immunohistochemistry revealed Mrp4 staining confined to centrilobular hepatocytes. Remarkably, Kupffer cell depletion completely prevented Mrp4 induction by APAP. Elevated plasma levels of TNF-α and IL-1β were also prevented by Kupffer cell depletion. These findings show that Kupffer cells protect the liver from APAP toxicity and that Kupffer cell mediators released in response to APAP are likely responsible for the induction of Mrp4.

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Donepudi, Ajay C., Michael J. Goedken, John D. Schuetz, and José E Manautou. "Lack of multidrug resistance-associated protein 4 (Mrp4) alters the kinetics of acetaminophen toxicity." Toxicology Reports 6 (2019): 841–49. http://dx.doi.org/10.1016/j.toxrep.2019.08.005.

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15

Hu, Haihong, Yu Wang, Zhiyuan Qin, Wen Sun, Yanhong Chen, Jiaqi Wang, Yingying Wang, et al. "Regulation of MRP4 Expression by circHIPK3 via Sponging miR-124-3p/miR-4524-5p in Hepatocellular Carcinoma." Biomedicines 9, no. 5 (April 30, 2021): 497. http://dx.doi.org/10.3390/biomedicines9050497.

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Multidrug resistance-associated protein 4 (MRP4), a member of the adenosine triphosphate (ATP) binding cassette transporter family, pumps various molecules out of the cell and is involved in cell communication and drug distribution. Several studies have reported the role of miRNAs in downregulating the expression of MRP4. However, regulation of MRP4 by circular RNA (circRNA) is yet to be elucidated. In this study, MRP4 was significantly upregulated in hepatocellular carcinoma (HCC) tissues compared to the adjacent noncancerous tissues. Computational prediction, luciferase reporter assay and miRNA transfection were used to investigate the interaction between miRNAs and MRP4. miR-124-3p and miR-4524-5p reduced the expression of MRP4 at the protein but not mRNA level. Circular RNA in vivo precipitation and luciferase reporter assays demonstrated that circHIPK3, as a competitive endogenous RNA, binds with miR-124-3p and miR-4524-5p. Further, knockdown of circHIPK3 resulted in downregulation of MRP4 protein, whereas cotransfection of circHIPK3-siRNA and miR-124-3p or miR-4524-5p inhibitors restored its expression. In conclusion, we report that miR-4524-5p downregulates the expression of MRP4 and circHIPK3 regulates MRP4 expression by sponging miR-124-3p and miR-4524-5p for the first time. Our results may provide novel insights into the prevention of MRP4-related proliferation and multiple drug resistance in HCC.

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Maher, J. M., X. Cheng, Y. Tanaka, G. L. Scheffer, and C. D. Klaassen. "Hormonal regulation of renal multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4) in mice." Biochemical Pharmacology 71, no. 10 (May 2006): 1470–78. http://dx.doi.org/10.1016/j.bcp.2006.02.005.

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17

Aleksunes, Lauren M., Sarah N. Campion, Michael J. Goedken, and José E. Manautou. "Acquired Resistance to Acetaminophen Hepatotoxicity is Associated with Induction of Multidrug Resistance-Associated Protein 4 (Mrp4) in Proliferating Hepatocytes." Toxicological Sciences 104, no. 2 (May 8, 2008): 261–73. http://dx.doi.org/10.1093/toxsci/kfn093.

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18

van Borselen, M., B. van Groen, J. Pertijs, M. Wilmer, B. Smeets, R. Verdijk, and S. de Wildt. "P98 Semi-quantification and localization of membrane transporters in paediatric kidney tissue." Archives of Disease in Childhood 104, no. 6 (May 17, 2019): e58.1-e58. http://dx.doi.org/10.1136/archdischild-2019-esdppp.136.

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BackgroundThe kidney has a critical role in disposition, efficacy and toxicity of drugs and xenobiotics. Developmental changes of renal membrane transporters have the potential to explain population variability in paediatric pharmacokinetics and -dynamics of drugs but data are missing. We aimed to further delineate the expression of human renal tubular transporters multidrug resistance-associated protein (MRP) 4 and MRP2 and study localization in paediatric kidney samples.MethodsWe planned to semi-quantify expression levels and to study the age-specific localization of the transporters MRP4 and MRP2 with immunohistochemistry on 44 human neonatal and paediatric kidney samples with age range of 24,00 - 40,00 weeks gestational age (GA) and 0,29 - 744 weeks post-natal age (PNA). The staining intensity was semi-quantitatively scored by two independent observers (MB and BG).ResultsMRP4 is found to be localized at the apical membrane of the renal proximal tubules at 27 weeks of GA (n=3, 1,29- 4 weeks PNA) and no age-related changes of expression levels were detected. In a premature neonate of 24 weeks GA (n=1), no MRP4 was detected. The MRP2 staining did not meet the requirements to be scored and was rejected.ConclusionMRP4 is expressed from at least 27 weeks GA onwards and does not show developmental changes. The localization was similar as in adults (Ritter et al., 2005). The half-life of the MRP4 substrate furosemide was found to be 6 to 20-fold longer in neonates than in adults (Pacifici, G.M., 2013). This could potentially be linked with the absence of MRP4 in a premature neonate with GA 24 weeks. However, these data should be confirmed as we only had 1 sample of ±24 weeks GA available. Moreover, our data help us in understanding altered disposition of transporter substrates in paediatrics.ReferencesPacifici, G. M. ( 2013). Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals;6(9):1094–1129.Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, Grube M, Köck K, & Kroemer HK. ( 2005). Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug metabolism reviews;37(1):253–278.Disclosure(s)Nothing to disclose

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RIGATO, Igino, Lorella PASCOLO, Cristina FERNETTI, J. Donald OSTROW, and Claudio TIRIBELLI. "The human multidrug-resistance-associated protein MRP1 mediates ATP-dependent transport of unconjugated bilirubin." Biochemical Journal 383, no. 2 (October 8, 2004): 335–41. http://dx.doi.org/10.1042/bj20040599.

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Results of previous studies have suggested that UCB (unconjugated bilirubin) may be transported by MRP1/Mrp1 (multidrug-resistance-associated protein 1). To test this hypothesis directly, [3H]UCB transport was assessed in plasma-membrane vesicles from MDCKII cells (Madin–Darby canine kidney II cells) stably transfected with human MRP1 or MRP2; wild-type MDCKII cells served as controls. As revealed by Western blotting, transfection achieved abundant expression of MRP1 and MRP2. [3H]UCB uptake was measured in the presence of 60 μM human serum albumin at a free (unbound) concentration of UCB (BF) ranging from 5 to 72 nM and in the presence of 3 mM ATP or 3 mM AMP-PCP (adenosine 5′-[β,γ-methylene]triphosphate). MRP1-transfected vesicles showed transport activity three and five times higher respectively compared with MRP2 or wild-type vesicles, whose transport did not differ significantly. [3H]UCB transport was stimulated 4-fold by 1.5 mM GSH, occurred into an osmotically sensitive space, was inhibited by 3 μM MK571 and followed saturative kinetics with Km=10±3 nM (BF) and Vmax=100±13 pmol·min−1·(mg of protein)−1. UCB significantly inhibited the transport of LTC4 (leukotriene C4), a leukotriene substrate known to have high affinity for MRP1. Collectively, these results prove directly that MRP1 mediates ATP-dependent cellular export of UCB and supports its role in protecting cells from bilirubin toxicity.

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Tchernychev, Boris, Pei Ge, Derek Wachtel, Robert Solinga, Marco Kessler, Sheila Ranganath, Gerhard Hannig, and Inmaculada Silos-Santiago. "Mo1886 Regulation of Linaclotide-Induced cGMP and Electrolyte Secretion by Multidrug Resistance-Associated Protein 4 (MRP4)." Gastroenterology 148, no. 4 (April 2015): S—735. http://dx.doi.org/10.1016/s0016-5085(15)32515-4.

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21

Brüggemann, Monika, Heiko Trautmann, Dieter Hoelzer, Michael Kneba, Nicola Gökbuget, and Thorsten Raff. "Multidrug resistance–associated protein 4 (MRP4) gene polymorphisms and treatment response in adult acute lymphoblastic leukemia." Blood 114, no. 26 (December 17, 2009): 5400–5401. http://dx.doi.org/10.1182/blood-2009-09-243741.

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22

Liu, Chengcheng, Laura J. Janke, Jun J. Yang, William E. Evans, John D. Schuetz, and Mary V. Relling. "Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity." Cancer Chemotherapy and Pharmacology 80, no. 2 (June 16, 2017): 287–93. http://dx.doi.org/10.1007/s00280-017-3361-2.

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23

Wittgen, Hanneke G. M., Jeroen J. M. W. van den Heuvel, Elmar Krieger, Gijs Schaftenaar, Frans G. M. Russel, and Jan B. Koenderink. "Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity." Biochemical Pharmacology 84, no. 3 (August 2012): 366–73. http://dx.doi.org/10.1016/j.bcp.2012.04.012.

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24

Montani, Matteo, Thomas Herrmanns, Michael Müntener, Peter Wild, Tullio Sulser, and Glen Kristiansen. "Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression." Virchows Archiv 462, no. 4 (March 16, 2013): 437–43. http://dx.doi.org/10.1007/s00428-013-1390-8.

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Longhi, Maria Serena, Anyan Xie, Rene’ J. Robles, Haohai Zhang, Eva Csizmadia, Yan Wu, Alan C. Moss, and Simon C. Robson. "Hypoxia boosts Th17-cell responses in inflammatory bowel disease through increased efflux of ligands reactive with the aryl-hydrocarbon-receptor." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 45.15. http://dx.doi.org/10.4049/jimmunol.200.supp.45.15.

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Abstract Despite beneficial influence of hypoxia-inducible-factor (HIF) stabilization in animal models of mucosal inflammation and experimental colitis, hypoxia can be deleterious during protracted inflammation by inhibiting T-regulatory-1 and favoring differentiation of T-helper (Th)-17 cells. We report here that Th17 cells from Crohn’s disease patients display heightened levels of HIF-1α and become refractory to the immunoregulatory effects of unconjugated bilirubin (UCB), an endogenous ligand for aryl hydrocarbon receptor (AhR), when exposed to hypoxia in vitro. Molecular blockade of HIF-1α reconstitutes Th17 cell ability to respond to UCB and upregulates CD39, an ectonucleotidase that catalyzes ATP and ADP into immunosuppressive adenosine. Inability of Th17 cells to respond to AhR derives from induction of ATP transporters multidrug-resistance-protein-1 (MDR1) and multidrug-resistance-associated-protein-4 (MRP4) by HIF-1α; this results in increased efflux of AhR ligands like UCB out of Th17 cells. Ritonavir, a drug with inhibitory effects over HIF-1α, MDR1 and MRP4, restores UCB regulation over Th17 cells in Crohn’s and enhances UCB salutary effects in dextran-sulfate-sodium-induced experimental colitis. We conclude that inhibitory effects of hypoxia in limiting Th17 cell response to AhR in Crohn’s disease are mediated through upregulation of ATP transporters that decrease AhR substrate availability. Concurrent treatment with HIF-1α inhibitors and AhR ligands provide effective therapeutic options to overcome Th17 functional alterations in inflammatory bowel disease.

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Billat, Pierre-André, Tahani Ossman, Franck Saint-Marcoux, Marie Essig, Jean-Philippe Rerolle, Nassim Kamar, Lionel Rostaing, et al. "Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients." Pharmacological Research 111 (September 2016): 501–8. http://dx.doi.org/10.1016/j.phrs.2016.07.012.

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Carozzo, Alejandro, Federico Diez, Natalia Gomez, Maia Cabrera, Carina Shayo, Carlos Davio, and Natalia Fernández. "Dual Role of cAMP in the Transcriptional Regulation of Multidrug Resistance-Associated Protein 4 (MRP4) in Pancreatic Adenocarcinoma Cell Lines." PLOS ONE 10, no. 3 (March 19, 2015): e0120651. http://dx.doi.org/10.1371/journal.pone.0120651.

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Scialis, Renato J., Carolina I. Ghanem, and José E. Manautou. "The modulation of transcriptional expression and inhibition of multidrug resistance associated protein 4 (MRP4) by analgesics and their primary metabolites." Current Research in Toxicology 1 (June 2020): 34–41. http://dx.doi.org/10.1016/j.crtox.2020.04.002.

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Yoshioka, Masakata, Hironori Sagara, Fumiyuki Takahashi, Norihiro Harada, Kazuto Nishio, Akio Mori, Hiroko Ushio, et al. "Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 1 (January 2009): L30—L36. http://dx.doi.org/10.1152/ajplung.00026.2008.

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Multidrug resistance-associated protein 1 (MRP1) is a cysteinyl leukotriene (CysLT) export pump expressed on mast cells. CysLTs are crucial mediators in allergic airway disease. However, biological significance of MRP1 in allergic airway inflammation has not yet been elucidated. In this study, we sensitized wild-type control mice ( mrp1+/+) and MRP1-deficient mice ( mrp1−/−) to ovalbumin (OVA) and challenged them with OVA by aerosol. Airway inflammation and goblet cell hyperplasia after OVA exposure were reduced in mrp1−/− mice compared with mrp1+/+ mice. Furthermore, CysLT levels in bronchoalveolar lavage fluid (BALF) from OVA-exposed mrp1−/− mice were significantly lower than those from OVA-exposed mrp1+/+ mice. Levels of OVA-specific IgE, IL-4, and IL-13 in BALF were also decreased in OVA-exposed mrp1−/− mice. IgE-mediated release of CysLTs from murine bone marrow-derived mast cells was markedly impaired by MRP1 deficiency. Our results indicate that MRP1 plays an important role in the development of allergic airway inflammation through regulation of IgE-mediated CysLT export from mast cells.

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Rakhila, Halima, Nathalie Bourcier, Ali Akoum, and Marc Pouliot. "Abnormal Expression of Prostaglandins E2 and F2αReceptors and Transporters in Patients with Endometriosis." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/808146.

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Objective.To investigate the level of expression of prostaglandin receptivity and uptake factors in eutopic and ectopic endometrium of women with endometriosis.Design.Prospective study.Setting.Human reproduction research laboratory.Patients.Seventy-eight patients with endometriosis and thirty healthy control subjects.Intervention(s).Endometrial and endometriotic tissue samples were obtained during laparoscopic surgery.Main Outcome Measure(s).Real-time polymerase chain reaction assay of mRNA encoding prostaglandin E2 receptors (EP1, EP2, EP3, and EP4), prostaglandin F2αreceptor (FP), prostaglandin transporter (PGT), and multidrug resistance-associated protein 4 (MRP4); immunohistochemical localization of expressed proteins.Results.Marked increases in receptors EP3, EP4, and FP and transporters PGT and MRP4 in ectopic endometrial tissue were noted, without noticeable change associated with disease stage. An increase in EP3 expression and decreases in FP and PGT were observed in the eutopic endometrium of endometriosis patients in conjunction with the phases of the menstrual cycle.Conclusion(s).This study is the first to demonstrate a possible relationship between endometriosis and enhanced prostaglandin activity. In view of the wide range of prostaglandin functions, increasing cell receptivity and facilitating uptake in endometrial tissue could contribute to the initial steps of overgrowth and have an important role to play in the pathogenesis and symptoms of this disease.

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Hoque, M. Tozammel, Olena Kis, María F. De Rosa, and Reina Bendayan. "Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters." Antimicrobial Agents and Chemotherapy 59, no. 5 (February 17, 2015): 2572–82. http://dx.doi.org/10.1128/aac.04594-14.

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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.

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Lacroix-Pépin, Nicolas, Ghislain Danyod, Narayanan Krishnaswamy, Sukanta Mondal, Pei-Min Rong, Pierre Chapdelaine, and Michel A. Fortier. "The Multidrug Resistance-Associated Protein 4 (MRP4) Appears as a Functional Carrier of Prostaglandins Regulated by Oxytocin in the Bovine Endometrium." Endocrinology 152, no. 12 (October 11, 2011): 4993–5004. http://dx.doi.org/10.1210/en.2011-1406.

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Imaoka, Tomoki, Hiroyuki Kusuhara, Masashi Adachi, John D. Schuetz, Kenji Takeuchi, and Yuichi Sugiyama. "Functional Involvement of Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in the Renal Elimination of the Antiviral Drugs Adefovir and Tenofovir." Molecular Pharmacology 71, no. 2 (November 16, 2006): 619–27. http://dx.doi.org/10.1124/mol.106.028233.

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Montani, Matteo, Thomas Hermanns, Michael Müntener, Peter Wild, Tullio Sulser, and Glen Kristiansen. "Erratum to: Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression." Virchows Archiv 463, no. 1 (June 1, 2013): 99. http://dx.doi.org/10.1007/s00428-013-1429-x.

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Li, Wan, Hua Sun, Xingwang Zhang, Huan Wang, and Baojian Wu. "Efflux transport of chrysin and apigenin sulfates in HEK293 cells overexpressing SULT1A3: The role of multidrug resistance-associated protein 4 (MRP4/ABCC4)." Biochemical Pharmacology 98, no. 1 (November 2015): 203–14. http://dx.doi.org/10.1016/j.bcp.2015.08.090.

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Sun, Hua, Xiao Wang, Xiaotong Zhou, Danyi Lu, Zhiguo Ma, and Baojian Wu. "Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) Controls Efflux Transport of Hesperetin Sulfates in Sulfotransferase 1A3–Overexpressing Human Embryonic Kidney 293 Cells." Drug Metabolism and Disposition 43, no. 10 (August 3, 2015): 1430–40. http://dx.doi.org/10.1124/dmd.115.065953.

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Mottino, Aldo D., Tim Hoffman, Lothar Jennes, Jingsong Cao, and Mary Vore. "Expression of multidrug resistance-associated protein 2 in small intestine from pregnant and postpartum rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 6 (June 1, 2001): G1261—G1273. http://dx.doi.org/10.1152/ajpgi.2001.280.6.g1261.

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We analyzed the expression of multidrug resistance-associated protein 2 (mrp2) in the small intestine of control female rats and in rats during late pregnancy (19–20 days of pregnancy) and lactation (2–4, 10–14, and 21 days after delivery). Western blot analysis was performed on brush-border membranes prepared from different regions of the small intestine. Expression of mrp2 was maximal in the proximal segments for all experimental groups, was preserved in pregnant rats, and increased by 100% in postpartum rats by late lactation with respect to control animals. Northern blot analysis of mrp2 mRNA revealed a positive correlation with protein levels. Transport of S-glutathione-dinitrophenol (DNP-SG) from the intestinal cell to the lumen was analyzed in the everted intestinal sac model. Secretion of DNP-SG was not altered in pregnant rats but increased in lactating animals by late lactation. Intestinal mrp2 mRNA, protein, and transport activity are increased in lactating rats, suggesting that this may represent an adaptive mechanism to minimize the toxicity of dietary xenobiotics in response to increased postpartum food consumption.

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Kis, Bela, Toyohi Isse, James A. Snipes, Lei Chen, Hiroshi Yamashita, Yoichi Ueta, and David W. Busija. "Effects of LPS stimulation on the expression of prostaglandin carriers in the cells of the blood-brain and blood-cerebrospinal fluid barriers." Journal of Applied Physiology 100, no. 4 (April 2006): 1392–99. http://dx.doi.org/10.1152/japplphysiol.01259.2005.

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Prostaglandins produced in cerebral endothelial cells (CECs) are the final signal transduction mediators from the periphery to the brain during fever response. However, prostaglandins are organic anions at physiological pH, and they enter cells poorly using simple diffusion. Several transporters have been described that specifically transport prostaglandins across cell membranes. We examined the expression of the two principal prostaglandin carriers, prostaglandin transporter (PGT), and multidrug resistance-associated protein 4 (MRP4) in cells of the blood-brain barrier and in choroid epithelial cells in vitro as well as in vivo in rat brain in control conditions and after lipopolysaccharide (LPS) challenge. We detected PGT in primary cultures of rat CECs, astrocytes, pericytes, and choroid epithelial cells. LPS stimulation had no effect on the expression level of PGT in these cells; however, after LPS stimulation the polarized, dominantly luminal, expression pattern of PGT significantly changed. MRP4 is also expressed in CECs, and its level was not influenced by LPS treatment. In rat brain, PGT was highly expressed in the supraoptic and paraventricular nuclei of the hypothalamus, in the ependymal cell layer of the third ventricle, and in the choroid plexus. LPS treatment increased the expression of PGT in the supraoptic and paraventricular nuclei. Our results suggest that PGT and MRP4 likely play a role in transporting prostaglandins through the blood-brain and blood-cerebrospinal fluid barriers and may be involved in the maintenance of prostaglandin homeostasis in the brain and in the initiation of fever response.

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Scharfman, Helen. "Upregulation of Multidrug Resistance Transporters in the Epileptic Brain." Epilepsy Currents 2, no. 6 (November 2002): 200. http://dx.doi.org/10.1111/j.1535-7597.2002.00076.x.

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Limbic Seizures Induce P-glycoprotein in Rodent Brain: Functional Implications for Pharmacoresistance Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D'Incalci M, Samanin R, Vezzani A J Neurosci 2002;22:5833–5839 The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug (AED) treatments in rodents enhance the brain expression of the MDR gene ( mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect AED concentrations in the brain. Mdr mRNA measured by reverse transcriptase–polymerase chain reaction (RT-PCR) increased by 85% on average in the mouse hippocampus 3–24 h after kainic acid–induced limbic seizures, returning to control levels by 72 h. Treatment with therapeutic doses of phenytoin (PHT) or carbamazepine (CBZ) for 7 days did not change mdr mRNA expression in the mouse hippocampus 1–72 h after the last drug administration. Six hours after seizures, the brain/plasma ratio of PHT was reduced by 30%, and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knockout mice (mdr1a/b_/_) lacking P-gp protein showed a 46% increase in PHT concentrations in the hippocampus 1 and 4 h after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 h and in the cortex at 4 h. CBZ concentrations were measurable in the hippocampus at 3 h in mdr1a/b_/_mice, whereas they were undetectable at the same interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect AED concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy. Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D Epilepsia 2001;42:1501–1506 Purpose It has been suggested that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue. Methods cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data. Results We found overexpression of selected MDR and significantly higher P-glycoprotein levels in “epileptic” versus “control” ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance-associated protein (hCRA-α) also was Conclusions Complex MDR expression changes may play a role in AED pharmacoresistance by altering the permeability of AEDs across the BBB. overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue.

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Li, Tiesong, Kousei Ito, and Toshiharu Horie. "Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 285, no. 3 (September 2003): G602—G610. http://dx.doi.org/10.1152/ajpgi.00424.2002.

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The transport characteristics of fluorescein methotrexate (F-MTX) were studied by using the rat intestinal crypt cell line IEC-6. Enhanced accumulation of F-MTX at 4°C suggests the existence of an active efflux system. MK-571, an inhibitor of the multidrug resistance-associated protein/ATP binding cassette C (MRP/ABCC) family, also enhanced the accumulation of F-MTX. Transcellular transport of F-MTX from the apical to the basolateral compartment was 2.5 times higher than the opposite direction. This vectorial transport was also reduced by MK-571, indicating the presence of Mrp-type transporter(s) on the basolateral membrane. Mrp3 mRNA was readily detectable, and the protein was localized on the basolateral membrane. Uptake of FMTX into membrane vesicles from IEC-6 cells and Spodoptera frugiperda-9 cells expressing rat Mrp3 were both ATP dependent and saturable as a function of the F-MTX concentration. Similar Km values (11.0 ± 1.8 and 4.5 ± 1.1 μM) and inhibition profiles by MK-571, estradiol-17β-d-glucuronide, and taurocholate for the ATP-dependent transport of F-MTX into these vesicles were obtained. These findings suggest that the efflux of F-MTX is mediated by Mrp3 on the basolateral membrane of IEC-6 cells.

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Bakos, E., R. Evers, G. Calenda, G. E. Tusnady, G. Szakacs, A. Varadi, and B. Sarkadi. "Characterization of the amino-terminal regions in the human multidrug resistance protein (MRP1)." Journal of Cell Science 113, no. 24 (December 15, 2000): 4451–61. http://dx.doi.org/10.1242/jcs.113.24.4451.

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The human multidrug resistance protein (MRP1) contributes to drug resistance in cancer cells. In addition to an MDR1-like core, MRP1 contains an N-terminal membrane-bound (TMD(0)) region and a cytoplasmic linker (L(0)), both characteristic of several members of the MRP family. In order to study the role of the TMD(0) and L(0) regions, we constructed various truncated and mutated MRP1, and chimeric MRP1-MDR1 molecules, which were expressed in insect (Sf9) and polarized mammalian (MDCKII) cells. The function of the various proteins was examined in isolated membrane vesicles by measuring the transport of leukotriene C(4) and other glutathione conjugates, and by vanadate-dependent nucleotide occlusion. Cellular localization, and glutathione-conjugate and drug transport, were also studied in MDCKII cells. We found that chimeric proteins consisting of N-terminal fragments of MRP1 fused to the N terminus of MDR1 preserved the transport, nucleotide occlusion and apical membrane routing of wild-type MDR1. As shown before, MRP1 without TMD(0)L(0) (Delta MRP1), was non-functional and localized intracellularly, so we investigated the coexpression of Delta MRP1 with the isolated L(0) region. Coexpression yielded a functional MRP1 molecule in Sf9 cells and routing to the lateral membrane in MDCKII cells. Interestingly, the L(0) peptide was found to be associated with membranes in Sf9 cells and could only be solubilized by urea or detergent. A 10-amino-acid deletion in a predicted amphipathic region of L(0) abolished its attachment to the membrane and eliminated MRP1 transport function, but did not affect membrane routing. Taken together, these experiments suggest that the L(0) region forms a distinct domain within MRP1, which interacts with hydrophobic membrane regions and with the core region of MRP1.

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Huang, Wen-Ge, Jun Wang, Yu-Juan Liu, Hong-Xia Wang, Si-Zhen Zhou, Huan Chen, Fang-Wan Yang, Ying Li, Yu Yi, and Yi-Huai He. "Endoplasmic Reticulum Stress Increases Multidrug-resistance Protein 2 Expression and Mitigates Acute Liver Injury." Current Molecular Medicine 20, no. 7 (July 24, 2020): 548–57. http://dx.doi.org/10.2174/1566524020666200124102411.

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Background: Multidrug-resistance protein (MRP) 2 is a key membrane transporter that is expressed on hepatocytes and regulated by nuclear factor kappa B (NF-κB). Interestingly, endoplasmic reticulum (ER) stress is closely associated with liver injury and the activation of NF-κB signaling. Objective: Here, we investigated the impact of ER stress on MRP2 expression and the functional involvement of MRP2 in acute liver injury. Methods: ER stress, MRP2 expression, and hepatocyte injury were analyzed in a carbon tetrachloride (CCl4)-induced mouse model of acute liver injury and in a thapsigargin (TG)-induced model of ER stress. Results: CCl4 and TG induced significant ER stress, MRP2 protein expression and NF- κB activation in mice and LO2 cells (P < 0.05). Pretreatment with ER stress inhibitor 4- phenyl butyric acid (PBA) significantly mitigated CCl4 and TG-induced ER stress and MRP2 protein expression (P < 0.05). Moreover, pretreatment with pyrrolidine dithiocarbamic acid (PDTC; NF-κB inhibitor) significantly inhibited CCl4-induced NF-κB activation and reduced MRP2 protein expression (1±0.097 vs. 0.623±0.054; P < 0.05). Furthermore, hepatic downregulation of MRP2 expression significantly increased CCl4- induced ER stress, apoptosis, and liver injury. Conclusion: ER stress enhances intrahepatic MRP2 protein expression by activating NF-κB. This increase in MRP2 expression mitigates ER stress and acute liver injury.

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Liu, Tong, Xiaojing Zhang, Yidan Zhang, Jiuzhou Hou, Dong Fang, Hua Sun, Qin Li, and Songqiang Xie. "Sulfation disposition of liquiritigenin in SULT1A3 overexpressing HEK293 cells: The role of breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4) in sulfate efflux of liquiritigenin." European Journal of Pharmaceutical Sciences 124 (November 2018): 228–39. http://dx.doi.org/10.1016/j.ejps.2018.08.041.

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Zhou, Xiaotong, Shaoxiang Wang, Hua Sun, and Baojian Wu. "Sulfonation of raloxifene in HEK293 cells overexpressing SULT1A3: Involvement of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in excretion of sulfate metabolites." Drug Metabolism and Pharmacokinetics 30, no. 6 (December 2015): 425–33. http://dx.doi.org/10.1016/j.dmpk.2015.09.001.

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Kawase, Atsushi, Yuta Inoue, Miho Hirosoko, Yuka Sugihara, Hiroaki Shimada, and Masahiro Iwaki. "Decrease in Multidrug Resistance-associated Protein 2 Activities by Knockdown of Phosphatidylinositol 4-phosphate 5-kinase in Hepatocytes and Cancer Cells." Journal of Pharmacy & Pharmaceutical Sciences 22 (November 19, 2019): 576–84. http://dx.doi.org/10.18433/jpps30444.

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Purpose: The plasma membrane localization and transport activity of multidrug resistance-associated protein 2 (MRP2/ABCC2) and P-glycoprotein (P-gp/ABCB1) efflux transporters are governed by transporter-associated proteins. Phosphatidylinositol 4,5-bisphosphate (PIP2) formed by phosphatidylinositol 4-phosphate 5-kinase type 1 (PIP5K1) activates the linker function of radixin for efflux transporters. Radixin is involved in the plasma membrane localization of efflux transporters. We examined whether PIP5K1 could be a target for the modulation of transporter activities in hepatocytes and cancer cells. Methods: The effects of PIP5K1 depletion by siRNA in mouse primary hepatocytes, PANC1 human pancreatic carcinoma cells, and HepG2 human hepatocellular carcinoma cells on the intracellular accumulation of MRP2 and P-gp substrates were examined. Results: PIP5K1A depletion resulted in increased intracellular accumulation of carboxydichlorofluorescein, a MRP2 fluorescent substrate, in mouse primary hepatocytes, PANC1 cells, and HepG2 cells. In PANC1 and HepG2 cells, the transport activities of MRP2 were significantly decreased by PIP5K1C depletion. However, the transport activities of P-gp were unchanged by PIP5K1 depletion. PIP2 levels were unchanged between control and PIP5K1A- or PIP5K1C-depleted HepG2 cells. MRP2 mRNA levels showed few changes in HepG2 cells following PIP5K1A or PIP5K1C depletion. The expression of phosphorylated radixin was decreased by PIP5K1A and PIP5K1C depletion, although total radixin levels were unchanged. Conclusions: These data suggest that PIP5K1A and PIP5K1C could be target proteins for modulating MRP2 function, partly because of the resulting changes of the linker function of radixin.

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Silverstein, Peter S., Kenneth L. Audus, Nilofer Qureshi, and Anil Kumar. "Lipopolysaccharide Increases the Expression of Multidrug Resistance-Associated Protein 1 (MRP1) in RAW 264.7 Macrophages." Journal of Neuroimmune Pharmacology 5, no. 4 (November 6, 2009): 516–20. http://dx.doi.org/10.1007/s11481-009-9180-4.

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Kanamitsu, Kayoko, Hiroyuki Kusuhara, John D. Schuetz, Kenji Takeuchi, and Yuichi Sugiyama. "Investigation of the Importance of Multidrug Resistance-Associated Protein 4 (Mrp4/ Abcc4 ) in the Active Efflux of Anionic Drugs Across the Blood–Brain Barrier." Journal of Pharmaceutical Sciences 106, no. 9 (September 2017): 2566–75. http://dx.doi.org/10.1016/j.xphs.2017.04.040.

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Tanaka, Yuji, Yoshinao Kobayashi, Esteban C. Gabazza, Kunihiro Higuchi, Toshinori Kamisako, Makoto Kuroda, Keisuke Takeuchi, Motoh Iwasa, Masahiko Kaito, and Yukihiko Adachi. "Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice." American Journal of Physiology-Gastrointestinal and Liver Physiology 282, no. 4 (April 1, 2002): G656—G662. http://dx.doi.org/10.1152/ajpgi.00383.2001.

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Regulation of bilirubin glucuronide transporters during hyperbilirubinemia in hepatic and extrahepatic tissues is not completely clear. In the present study, we evaluated the regulation of the bilirubin glucuronide transporters, multidrug resistance-associated proteins (MRP)2 and 3, in rats with obstructive jaundice. Bile duct ligation (BDL) or sham operation was performed in Wistar rats. Liver and kidneys were removed 1, 3, and 5 days after BDL ( n = 4, in each group). Serum and urine were collected to measure bilirubin levels just before animal killing. MRP2 And MRP3 mRNA expressions were determined by real-time RT-PCR. Protein expression of MRP2 and MRP3 was determined by Western blotting. Renal MRP2 function was evaluated by para-aminohippurate (PAH) clearance. The effect of conjugated bilirubin, unconjugated bilirubin, human bile, and sulfate-conjugated bile acid on MRP2 gene expression was also evaluated in renal and hepatocyte cell lines. Serum bilirubin and urinary bilirubin excretion increased significantly after BDL. In the liver, the mRNA expression of MRP2 decreased 59, 86, and 82%, and its protein expression decreased 25, 74, and 93% compared with sham-operated animals after 24, 72, and 120 h of BDL, respectively. In contrast, the liver expression of MRP3 mRNA increased 138, 2,137, and 3,295%, and its protein expression increased 560, 634, and 612% compared with sham-operated animals after 24, 72, and 120 h of BDL, respectively. On the other hand, in the kidneys, the mRNA expression of MRP2 increased 162, 73, and 21%, and its protein expression increased 387, 558, and 472% compared with sham-operated animals after 24, 72, and 120 h of BDL, respectively. PAH clearance was significantly increased after BDL. The mRNA expression of MRP2 increased in renal proximal tubular epithelial cells after treatment with conjugated bilirubin, sulfate-conjugated bile acid or human bile. Upregulation of MRP2 in the kidneys and MRP3 in the liver may be a compensatory mechanism to improve bilirubin clearance during obstructive jaundice.

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Kopanitsa, Liliya, Maksym V. Kopanitsa, Dewi Safitri, Graham Ladds, and David S. Bailey. "Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition." International Journal of Molecular Sciences 22, no. 18 (September 7, 2021): 9665. http://dx.doi.org/10.3390/ijms22189665.

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Abstract:

The paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined the effects of 28 PDE inhibitors, covering all the major PDE classes, on the proliferation of the human U87MG, A172 and T98G glioblastoma cells. The PDE10A inhibitors PF-2545920, PQ10 and papaverine, the PDE3/4 inhibitor trequinsin and the putative PDE5 inhibitor MY-5445 potently decreased glioblastoma cell proliferation. The synergistic suppression of glioblastoma cell proliferation was achieved by combining PF-2545920 and MY-5445. Furthermore, a co-incubation with drugs that block the activity of the multidrug resistance-associated protein 1 (MRP1) augmented these effects. In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy.

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Geier, Andreas, Christoph G. Dietrich, Sebastian Voigt, Meenakshisundaram Ananthanarayanan, Frank Lammert, Anne Schmitz, Michael Trauner, et al. "Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 5 (November 2005): G831—G841. http://dx.doi.org/10.1152/ajpgi.00307.2004.

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Abstract:

Proinflammatory cytokines such as TNF-α and IL-1β lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-α or IL-1β for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-α induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1β also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1α sites after 4 h by either cytokine, which remained more sustained by TNF-α in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-α are significantly decreased by TNF-α but only transiently affected by IL-1β. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-α and IL-1β. Activity of HNF-1α as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-α.

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