Journal articles: 'ABCC3'

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Leprohon, Philippe, Danielle Légaré, and Marc Ouellette. "Intracellular Localization of the ABCC Proteins of Leishmania and Their Role in Resistance to Antimonials." Antimicrobial Agents and Chemotherapy 53, no. 6 (2009): 2646–49. http://dx.doi.org/10.1128/aac.01474-08.

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ABSTRACT The ABCC subfamily of proteins is composed of nine members in Leishmania. We report that all of these proteins have an intracellular localization and that the overexpression of at least four members, ABCC3, ABCC4, ABCC5, and ABCC7, can confer resistance to antimonials, the first-line drug against Leishmania.

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Ghanem, Carolina I., and Jose E. Manautou. "Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics." Current Medicinal Chemistry 26, no. 7 (2019): 1185–223. http://dx.doi.org/10.2174/0929867325666180221142315.

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Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into &quot;long&quot; (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and &quot;short&quot; (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.

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Norris, M. D., J. Smith, A. Kwek, et al. "Expression of the multidrug transporter genes ABCC1/MRP1, ABCC3/MRP3, and ABCC4/MRP4 are powerful predictors of clinical outcome in childhood neuroblastoma." Journal of Clinical Oncology 25, no. 18_suppl (2007): 9524. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.9524.

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9524 Background: We have previously shown, both retrospectively and prospectively, that high-level expression of the multidrug transporter gene ABCC1/MRP1, is strongly predictive of poor outcome in the childhood cancer neuroblastoma (NEJM, 334:231–8, 1996; JCO, 24:1546–53, 2006), and that ABCC1/MRP1 can be regulated by the MYCN oncogene. The contribution of other ABCC family genes to clinical outcome in this disease has now been examined. Methods: Real-time quantitative PCR was used to determine ABCC gene expression in a large prospectively accrued cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Results: Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in the cohort. Amongst the ABCC family, high levels of ABCC1 and ABCC4, but low levels of ABCC3, were strongly associated with reduced survival and event-free survival (P<0.005) in the overall study population, and also in subgroups of patients lacking MYCN amplification. Following adjustment for the effect of MYCN gene amplification and other prognostic indicators by multivariate analysis, expression of ABCC1 (HR=2.3; p=0.03), ABCC3 (HR=2.7; p=0.0141), ABCC4 (HR=3.4; p=0.002) retained significant prognostic value for outcome, whereas age and MYCN amplification lost all prognostic significance. By combining the expression of these three transporter genes, patients could be stratified into groups having excellent, intermediate or poor outcome (EFS=84%, 59%, 17%, respectively). Conclusions: These data, suggest that ABCC1, 3 and 4 are amongst the most powerful prognostic markers yet identified for childhood neuroblastoma and as such represent important targets for potential therapeutic intervention. No significant financial relationships to disclose.

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Malinowski, Damian, Paweł Grzegółkowski, Katarzyna Piotrowska, Marcin Słojewski, and Marek Droździk. "Membrane Transporters and Carriers in Human Seminal Vesicles." Journal of Clinical Medicine 11, no. 8 (2022): 2213. http://dx.doi.org/10.3390/jcm11082213.

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Seminal vesicles play an important role in the male reproductive system, producing seminal fluid and thus adequate environment for sperm. However, mechanisms underlying secretory functions of the seminal vesicles’ epithelium have not been defined yet. The aim of the present study was to characterize expression and immunolocalization of selected membrane transporters and carriers in the seminal vesicles. The study included biopsy specimens collected from non-affected parts of seminal vesicles from 53 patients of Caucasian origin subjected for prostatectomy. RT-PCR was used to define expression of 15 genes coding for ABC-family and 37 genes encoding 37 SLC-family transporters/carriers. Immunohistochemistry was used to define localization of 6 transporters. In the seminal vesicles, the following membrane transporters and carriers were defined: ABCA1, ABCB1, ABCB5, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCG2, SLC01C1, SLC02B1, SLC04A1, SLC04C1, SLC10A1, SLC15A1, SLC15A2, SLC16A1, SLC16A3, SLC19A1, SLC22A1, SLC22A3, SLC22A11, SLC22A18, SLC22A4, SLC22A5, SLC28A1, SLC2A9, SLC33A1, SLC47A1, SLC47A2, SLC51A, SLC51B, SLC7A5, SLC7A6. Age-dependent expression was evidenced for ABCB1, ABCG2, SLC04C1, SLC15A1, SLC16A1, SLC22A11, SLC22A18, SLC47A1 and SLC47A2. ABCG2, P-gp, MRP1, MRP3, MCT1 and LAT1 were localized in the apical membrane and P-gp in the basolateral membrane of the seminal vesicle epithelium. The expression of the membrane transporters and carriers in the seminal vesicle epithelium confirms its secretory and barrier functions.

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Encarnación-Medina, Jarline, Rosa I. Rodríguez-Cotto, Joseph Bloom-Oquendo, Mario G. Ortiz-Martínez, Jorge Duconge, and Braulio Jiménez-Vélez. "Selective ATP-Binding Cassette Subfamily C Gene Expression and Proinflammatory Mediators Released by BEAS-2B after PM2.5, Budesonide, and Cotreated Exposures." Mediators of Inflammation 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/6827194.

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ATP-binding cassette subfamily C (ABCC) genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5)) and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1–4 gene expression changes and proinflammatory cytokine (IL-6, IL-8) release in human bronchial epithelial cells (BEAS-2B) exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients), and a cotreatment (Co-T: PM2.5 and BUD). A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM2.5.

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Falasca, Marco, Xi Chen, and Gary Piazza. "Abstract 1814: Novel ABC transport inhibitor as a treatment for pancreatic and prostate cancers." Cancer Research 82, no. 12_Supplement (2022): 1814. http://dx.doi.org/10.1158/1538-7445.am2022-1814.

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Abstract ABC transporters are the active transport systems of the cell involved in the export or import of a wide variety of molecules. We discovered that a member of the ABC transporter family called ABCC3 has a critical role in pancreatic cancer. ABCC3 blockade using genetic knockdown inhibits pancreatic cancer growth in vitro and in vivo. In addition, we demonstrate that knockdown of ABCC3 reduces cell proliferation by inhibition of STAT3 and HIF1α signalling pathways, which are key regulators of pancreatic cancer progression. A focused chemical library of indenes was screened for ABCC3 inhibition using ABCC3 expressing pancreatic tumour cells. A drug development candidate, designated as S3, emerged following extensive chemical modification to optimize target selectivity and oral bioavailability. Oral administration of S3 significantly inhibited tumour growth and increased survival in several mouse models of pancreatic cancer without discernible toxicity. Interestingly, using the KPC transgenic mouse model that closely mimics human pancreatic cancer, we identified a dual activity of S3 to inhibit the growth of the primary tumour and impact the surrounding stroma. Strikingly, a significant increase in survival was achieved with S3 treatment compared to vehicle treated KPC mice. A two-fold increase in lifespan was observed from 72.5 days (median survival) in the control group to 146.5 days in the treatment group. Importantly, we observed no overt toxicity from S3 treatment at a dosage of 50 mg/kg, which generated plasma levels exceeding growth inhibitory IC50 values. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in cancer progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming. In other studies, we found that S3 inhibits the closely related transporter, ABCC1, and that pharmacological inhibition of ABCC1 reduced prostate cancer cell growth in vitro and potentiated the effects of Docetaxel in vitro and in mouse models of prostate cancer in vivo. Mechanistically, we have shown that ABCC3, is overexpressed in pancreatic cancer cells and can efflux the bioactive lipid lysophosphatidylinositol (LPI) which, in turn, activates its receptor G protein-coupled receptor 55 in an autocrine mitogenic loop. Similarly, ABCC1 mediates LPI efflux in prostate cancer cells. The fact that both ABCC1 and ABCC3 transport LPI and are inhibited by S3 is not surprising considering that they share a high primary sequence identity and are known to have overlapping substrate specificity. Interestingly, unlike known ABC inhibitors, S3 has anticancer activity as a single agent. Our goal is to further study the antitumor activity of S3 alone and in combination with conventional chemotherapy or molecular targeted drugs used for the treatment of pancreatic and prostate cancer. Citation Format: Marco Falasca, Xi Chen, Gary Piazza. Novel ABC transport inhibitor as a treatment for pancreatic and prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1814.

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Leprohon, Philippe, Danielle Légaré, Isabelle Girard, Barbara Papadopoulou, and Marc Ouellette. "Modulation of Leishmania ABC Protein Gene Expression through Life Stages and among Drug-Resistant Parasites." Eukaryotic Cell 5, no. 10 (2006): 1713–25. http://dx.doi.org/10.1128/ec.00152-06.

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ABSTRACT The ATP-binding cassette (ABC) protein superfamily is one of the largest evolutionarily conserved families and is found in all kingdoms of life. The recent completion of the Leishmania genome sequence allowed us to analyze and classify its encoded ABC proteins. The complete sequence predicts a data set of 42 open reading frames (ORFs) coding for proteins belonging to the ABC superfamily, with representative members of every major subfamily (from ABCA to ABCH) commonly found in eukaryotes. Comparative analysis showed that the same ABC data set is found between Leishmania major and Leishmania infantum and that some orthologues are found in the genome of the related parasites Trypanosoma brucei and Trypanosoma cruzi. Customized DNA microarrays were made to assess ABC gene expression profiling throughout the two main Leishmania life stages. Two ABC genes (ABCA3 and ABCG3) are preferentially expressed in the amastigote stage, whereas one ABC gene (ABCF3) is more abundantly expressed in promastigotes. Microarray-based expression profiling experiments also revealed that three ABC genes (ABCA3, ABCC3, and ABCH1) are overexpressed in two independent antimony-resistant strains compared to the parental sensitive strain. All microarray results were confirmed by real-time reverse transcription-PCR assays. The present study provides a thorough phylogenic classification of the Leishmania ABC proteins and sets the basis for further functional studies on this important class of proteins.

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Iraci, Nunzio, Simona Soverini, Samuele Gherardi, et al. "Expression Profiling of ABC Transporter Genes in Chronic Myeloid Leukemia (CML) and Responsiveness to Imatinib." Blood 112, no. 11 (2008): 3193. http://dx.doi.org/10.1182/blood.v112.11.3193.3193.

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Abstract The deregulation of ATP-binding cassette (ABC) transporters responsible for the efflux of anticancer agents may involve mutations or single nucleotide polymorphisms (SNPs) or an increase in their expression level. Consequently, chemoresistance may develop. We have previously shown that the expression level and transcription of ABC drug transporters in CML cells is affected by c-Myc. Our results demonstrated that c-Myc is highly expressed in CD34+ cells from newly diagnosed chronic phase (CP)-CML patients, and that it can significantly upregulate the expression of several ABC genes, particularly, the ABCC1, ABCC4 and ABCG2, while it downregulates the expression of ABCC3. We have also demonstrated that c-Myc was a direct regulator and physically associated with the promoter of tested ABC genes, as assessed by Chromatin Immunoprecipitation in a cell line derived from a Ph+ CML patient. Taken together, our findings supported the model of a direct and coordinate regulation of a large set of ABC genes by the c-Myc transcription factor. Our study also supported prior findings that deregulation of specific set of ABC genes could be an important molecular mechanism altering imatinib transport. Based on these observations we have started to investigate the role of ABC transport genes expression in newly diagnosed CP-CML patients treated with imatinib. RNA extracted from white blood cells of 5 patients who achieved a stable major molecular response (MMR) by 12 months (responders) and 15 patients who didn’t show a partial cytogenetic response (CgR) by 6 months nor a complete CgR by 12 months (suboptimal responders according to European LeukemiaNet recommendations). All pts were enrolled on GIMEMA CML Working Party-sponsored clinical trials of imatinib. A panel of ABC genes including ABCB1, ABCB9, ABCC1, ABCC3, ABCC4, ABCE1 and ABCG2 was interrogated by Q-PCR for the level of expression. Results were normalized to the expression of three reference genes, i.e., GUSB, b-actin and GAPDH. Our results show that suboptimal responders display high expression levels of ABCG2 (p&lt;0.01) and very low levels of ABCC3 (p&lt;0.0001) as compared to patients with responders. Interestingly, when ABC expression profile of the same patient was evaluated before starting imatinib treatment and compared with a measurement obtained at the time of suboptimal response, we could not observe any significant difference between the two conditions. That suggest that this specific ABC transporter expression profile could be present at diagnosis. Although preliminary, our findings suggest that profiling of ABC drug transporter genes in CML patients could provide a novel modality of investigating their responsiveness to imatinib. Analysis of a larger series of patients is ongoing to further explore the potential predictive value of this expression profile. We speculate that ABCC3, which is strongly repressed possibly through a typical epigenetic mechanisms such as promoter hypermethylation and/or chromatin condensation, could be re-activated by means of demethylating agents or inhibitors of chromatin condensation. Thus, our study proposes that an important novel approach to optimize imatinib response in such patients merits further investigations.

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Mutch, David M., Pascale Anderle, Muriel Fiaux, et al. "Regional variations in ABC transporter expression along the mouse intestinal tract." Physiological Genomics 17, no. 1 (2004): 11–20. http://dx.doi.org/10.1152/physiolgenomics.00150.2003.

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The ATP-binding cassette (ABC) family of proteins comprise a group of membrane transporters involved in the transport of a wide variety of compounds, such as xenobiotics, vitamins, lipids, amino acids, and carbohydrates. Determining their regional expression patterns along the intestinal tract will further characterize their transport functions in the gut. The mRNA expression levels of murine ABC transporters in the duodenum, jejunum, ileum, and colon were examined using the Affymetrix MuU74v2 GeneChip set. Eight ABC transporters (Abcb2, Abcb3, Abcb9, Abcc3, Abcc6, Abcd1, Abcg5, and Abcg8) displayed significant differential gene expression along the intestinal tract, as determined by two statistical models (a global error assessment model and a classic ANOVA, both with a P < 0.01). Concordance with semiquantitative real-time PCR was high. Analyzing the promoters of the differentially expressed ABC transporters did not identify common transcriptional motifs between family members or with other genes; however, the expression profile for Abcb9 was highly correlated with fibulin-1, and both genes share a common complex promoter model involving the NFκB, zinc binding protein factor (ZBPF), GC-box factors SP1/GC (SP1F), and early growth response factor (EGRF) transcription binding motifs. The cellular location of another of the differentially expressed ABC transporters, Abcc3, was examined by immunohistochemistry. Staining revealed that the protein is consistently expressed in the basolateral compartment of enterocytes along the anterior-posterior axis of the intestine. Furthermore, the intensity of the staining pattern is concordant with the expression profile. This agrees with previous findings in which the mRNA, protein, and transport function of Abcc3 were increased in the rat distal intestine. These data reveal regional differences in gene expression profiles along the intestinal tract and demonstrate that a complete understanding of intestinal ABC transporter function can only be achieved by examining the physiologically distinct regions of the gut.

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Franz, Laura, Klaus Raming, and Ralf Nauen. "Recombinant Expression of ABCC2 Variants Confirms the Importance of Mutations in Extracellular Loop 4 for Cry1F Resistance in Fall Armyworm." Toxins 14, no. 2 (2022): 157. http://dx.doi.org/10.3390/toxins14020157.

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Fall armyworm (FAW), Spodoptera frugiperda, is a highly destructive and invasive global noctuid pest. Its control is based on insecticide applications and Bacillus thuringiensis (Bt) insecticidal Cry toxins expressed in transgenic crops, such as Cry1F in Bt corn. Continuous selection pressure has resulted in populations that are resistant to Bt corn, particularly in Brazil. FAW resistance to Cry1F was recently shown to be conferred by mutations of ATP-binding cassette transporter C2 (ABCC2), but several mutations, particularly indels in extracellular loop 4 (ECL4), are not yet functionally validated. We addressed this knowledge gap by baculovirus-free insect cell expression of ABCC2 variants (and ABCC3) by electroporation technology and tested their response to Cry1F, Cry1A.105 and Cry1Ab. We employed a SYTOXTM orange cell viability test measuring ABCC2-mediated Bt toxin pore formation. In total, we tested seven different FAW ABCC2 variants mutated in ECL4, two mutants modified in nucleotide binding domain (NBD) 2, including a deletion mutant lacking NBD2, and S. frugiperda ABCC3. All tested ECL4 mutations conferred high resistance to Cry1F, but much less to Cry1A.105 and Cry1Ab, whereas mutations in NBD2 hardly affected Bt toxin activity. Our study confirms the importance of indels in ECL4 for Cry1F resistance in S. frugiperda ABCC2.

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Lecoeur, Sylvaine, Bernadette Videmann, Michele Mazallon, and Marcel Delaforge. "The mycotoxin zearalenone and its metabolites specifically interact with transporter proteins ABCC1, ABCC2, and ABCC3." Toxicology Letters 189 (September 2009): S75. http://dx.doi.org/10.1016/j.toxlet.2009.06.225.

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Sun, Zelin, Xiaoyuan Qi, and Yan Zhang. "Bioinformatics Analysis of the Expression of ATP binding cassette subfamily C member 3 (ABCC3) in Human Glioma." Open Medicine 15, no. 1 (2020): 107–13. http://dx.doi.org/10.1515/med-2020-0016.

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AbstractObjectiveTo investigate the expression of the ABCC3 gene in human glioma and its correlation with the patient’s prognosis.MethodsThe cancer genome atlas (TCGA) database was used to analyze the differential expression of the ABCC3 gene in human glioma. The STRING database was used to construct the protein-protein interaction (PPI) network of the ABCC3 gene coding protein. The co-expression genes relevant to the ABCC3 gene were analyzed by the Pearson correlation test. A log-rank test was used to analyze the difference of overall survival (OS) and disease-free survival (DFS) between the high and low ABCC3 gene expression groups.ResultsThe expression level of the ABCC3 gene in glioma tissues was lower than that of corresponding normal brain tissues. The PPI network contains 51 nodes with the average node degree of 13.3 and the local clustering coefficient of 0.72 which indicated that the PPI enrichment was significant (p<0.001). Ten hub genes (ABCC3,NR1I2,NR1H4,-CYP7A1,SLC10A1,CYP3A4,UGT1A1,UGT1A8,UGT1A6 and ALB) were identified by the cytoscape software. The KEGG analysis was enriched in drug metabolism - cytochrome P450 and PPAR signaling pathway. CFI gene expression level was positive correlated with the ABCC3 expression level (r=0.71, p<0.05). And the CNRIP1 gene expressed was negative correlated with ABCC3 expression (r=-0.43, p<0.05). The overall survival (HR=2.8, P<0.05) and disease-free survival rates (HR=2.0, P<0.05) of patients with ABCC3 low expression glioma were significantly higher than those of patients with high expression of ABCC3. Conclusion The expression level of the ABCC3 gene in glioma was decreased compared to normal brain tissue. The overall survival and disease-free survival of in the ABCC3 low-expression group was significant decreased.

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Li, Qiaoli, Qiujie Jiang, Jennifer LaRusso, et al. "Targeted ablation of Abcc1 or Abcc3 in Abcc6−/− mice does not modify the ectopic mineralization process." Experimental Dermatology 16, no. 10 (2007): 853–59. http://dx.doi.org/10.1111/j.1600-0625.2007.00621.x.

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de Waart, Dirk R., Koen van de Wetering, Cindy Kunne, Suzanne Duijst, Coen C. Paulusma, and Ronald P. J. Oude Elferink. "Oral Availability of Cefadroxil Depends on ABCC3 and ABCC4." Drug Metabolism and Disposition 40, no. 3 (2011): 515–21. http://dx.doi.org/10.1124/dmd.111.041731.

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Pellegatta, Ianni, Pessina, et al. "ABCC3 Expressed by CD56dim CD16+ NK Cells Predicts Response in Glioblastoma Patients Treated with Combined Chemotherapy and Dendritic Cell Immunotherapy." International Journal of Molecular Sciences 20, no. 23 (2019): 5886. http://dx.doi.org/10.3390/ijms20235886.

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Recently, we found that temozolomide (TMZ) can upregulate the expression of the multidrug-resistance protein ABCC3 in NK cells from both glioma-bearing mice and glioblastoma patients treated with dendritic cell immunotherapy combined with TMZ, allowing NK cells to escape apoptosis and favoring their role as antitumor effector cells. Here, we demonstrate that CD56dim NK cells expressing CD16+ are predominant in patients surviving more than 12 months after surgery without disease progression. CD56dim CD16+ NK cells co-expressed high levels of ABCC3 and IFN-. Notably, not only basal but also TMZ-induced ABCC3 expression was related to a strong, long-term NK cell response and a better prognosis of patients. The identification of the single nucleotide polymorphism (SNP) rs35467079 with the deletion of a cytosine (−897DelC) in the promoter region of the ABCC3 gene resulted associated with a better patient outcome. ABCC3 expression in patients carrying DelC compared to patients with reference haplotype was higher and modulated by TMZ. The transcription factor NRF2, involved in ABCC3 induction, was phosphorylated in CD56dim CD16+ NK cells expressing ABCC3 under TMZ treatment. Thus, ABCC3 protein and the SNP −897DelC can play a predictive role in patients affected by GBM, and possibly other cancers, treated with dendritic cell immunotherapy combined with chemotherapy.

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Hu, Ya-Hui, Lin Zhou, Shan-Shan Wang, et al. "Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters." Current Pharmaceutical Design 25, no. 6 (2019): 627–34. http://dx.doi.org/10.2174/1381612825666190329141003.

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Background: Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment. Methods: We searched PubMed for citations published in English using the terms “methotrexate”, “transporter”, “acute lymphoblastic leukemia”, “polymorphisms”, and “therapeutic drug monitoring”. The retrieval papers were critically reviewed and summarized according to the aims of this mini-review. Results: Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied. Conclusion: Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.

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Fang, Dan-Dong, Wei Huang, Gang Cheng, et al. "Clinicopathological and Prognostic Significance of ABCC3 in Human Glioma." Journal of Oncology 2021 (December 23, 2021): 1–8. http://dx.doi.org/10.1155/2021/1827992.

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Glioma is the most common malignant primary brain tumor with an inferior survival period and unsatisfactory prognoses. Identification of novel biomarkers is important for the improvements of clinical outcomes of glioma patients. In recent years, more and more biomarkers were identified in many types of tumors. However, the sensitive markers for diagnoses and prognoses of patients with glioma remained unknown. In the present research, our team intended to explore the expression and clinical significance of ABCC3 in glioma patients. Sequential data filtration (survival analyses, independent prognosis analyses, ROC curve analyses, and clinical association analyses) was completed, which gave rise to the determination of the relationship between glioma and the ABCC3 gene. Clinical assays on the foundation of CGGA and TCGA datasets unveiled that ABCC3 expression was distinctly upregulated in glioma and predicted a shorter overall survival. In the multivariable Cox analysis, our team discovered that the expression of ABCC3 was an independent prognosis marker for both 5-year OS (HR = 1.118, 95% CI: 1.052–1.188; P < 0.001 ). Moreover, our team also studied the association between ABCC3 expression and clinical features of glioma patients, finding that differential expression of ABCC3 was remarkably related to age, 1p19q codeletion, PRS type, chemo status, grade, IDH mutation state, and histology. Overall, our findings suggested ABCC3 might be a novel prognosis marker in glioma.

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Weiss, Johanna, Dirk Theile, Nahal Ketabi-Kiyanvash, Heike Lindenmaier, and Walter Emil Haefeli. "Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by Nucleoside, Nucleotide, and Non-Nucleoside Reverse Transcriptase Inhibitors." Drug Metabolism and Disposition 35, no. 3 (2006): 340–44. http://dx.doi.org/10.1124/dmd.106.012765.

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Mooij, Miriam, Evita Van de Steeg, Heleen Wortelboer, Wouter Vaes, Dick Tibboel, and Saskia De Wildt. "HEPATIC TRANSPORTER PROTEIN EXPRESSION IN FETUSES, NEONATES AND YOUNG INFANTS." Archives of Disease in Childhood 101, no. 1 (2015): e1.23-e1. http://dx.doi.org/10.1136/archdischild-2015-310148.3.

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BackgroundTransporters are membrane-bound proteins involved in trafficking substrates (e.g. drugs) across membranes of among others hepatocytes. Limited data exists on the developmental expression. We aim to study protein expression of transporters in fetal, neonatal and infantile liver.MethodsTransporter protein expression (ABCB1, ABCG2, ABCC2, ABCC3, BSEP, GLUT1, MCT1, OATP1B1, OATP2B1, OCTN2) was quantified using UPLC-MS-MS, on snap-frozen post mortem livers (Erasmus MC tissuebank) and adult control livers (UMC-Groningen). Protein expression was determined in isolated crude membrane and quantified using stable-isotope-labelled peptides. Age groups were compared with Mann-Whitney test and post hoc Bonferroni-correction (significance p<0.05). Data was compared to mRNA expression.Results25 liver samples were studied. 10 fetal [median gestational age 23.2 weeks (range 16.4–37.9)], 12 pediatric [postnatal age 1 week (0–11.4) and gestational age at birth 35.1 weeks (27.1–41.0)], and 3 adult liver samples. ABCB1, ABCC2, OATP1B1, OATP2B1 expressions appeared similar in fetuses, pediatrics and adults. MCT1 expression was similar in fetuses and adults, but higher in pediatrics. BSEP expression was lower in fetuses and pediatrics than in adults. ABCC3 expression was lower level in fetuses than in adults, but not in pediatrics compared to adults. ABCG2, GLUT1, OCTN2 expressions were higher in fetuses than in adults, but similar in pediatrics and adults.ConclusionHepatic transporters appear in different developmental expression profiles. ABCB1, ABCC2, OATP1B1 protein expression appears stable. This contrast previous mRNA expression data, which showed lower expression in fetus/neonate. The age-related differences in transporter expression may result in age-dependent pharmacokinetics of substrates.

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Bousquet, Laurence, Alain Pruvost, Anne-Cécile Guyot, Robert Farinotti, and Aloïse Mabondzo. "Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation." Antimicrobial Agents and Chemotherapy 53, no. 3 (2008): 896–902. http://dx.doi.org/10.1128/aac.00733-08.

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ABSTRACT Efflux proteins have been shown to greatly affect the uptake of antiretroviral drugs by cells and to hamper their access to the human immunodeficiency virus type 1 replication site. This study evaluated the factors that may lead to drug-drug interactions between emtricitabine (FTC), tenofovir (TFV), and efavirenz (EFV), including the modulation of efflux transporter expression and function. Peripheral blood mononuclear cells from healthy volunteers were used to determine whether or not an interaction between antiretroviral drugs and target cells occurred in any combination of FTC, TFV, EFV, FTC-TFV, TFV-EFV, or FTC-TFV-EFV. Following 20 h of treatment, intracellular drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Efflux transporter functionality and inhibitor drug properties were assessed by measuring fluorescent dye efflux. ABCB1 (P-glycoprotein), ABCC 1 to 6 (multidrug resistance-associated protein), and OAT (organic anion transporter) expression in response to the treatments was quantified by semiquantitative real-time PCR. Cells treated with a double combination (FTC-TFV or TFV-EFV) or the triple combination (FTC-TFV-EFV) produced higher FTC and TFV intracellular concentrations than cells treated with FTC or TFV alone. However, no change in the EFV intracellular concentration was observed. FTC tended to induce abcc5 mRNA expression and EFV tended to induce abcc1 and abcc6 mRNA expression, whereas TFV tended to reduce mdr1, abcc1, abcc5, and abcc6 mRNA expression. Under these conditions, a decrease in the functionality of ABCC was observed, and this decrease was associated with the direct inhibitory actions of these drugs. This in vitro study reveals a benefit of the combination FTC-TFV-EFV in terms of the intracellular FTC and TFV concentrations and highlights the pharmacological mechanisms that lead to this effect.

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de Waart, Dirk R., Maria L. H. Vlaming, Cindy Kunne, Alfred H. Schinkel, and Ronald P. J. Oude Elferink. "Complex Pharmacokinetic Behavior of Ezetimibe Depends on Abcc2, Abcc3, and Abcg2." Drug Metabolism and Disposition 37, no. 8 (2009): 1698–702. http://dx.doi.org/10.1124/dmd.108.026146.

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Videmann, Bernadette, M. Mazallon, C. Prouillac, Marcel Delaforge, and Sylvaine Lecoeur. "ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites." Toxicology Letters 190, no. 2 (2009): 215–23. http://dx.doi.org/10.1016/j.toxlet.2009.07.021.

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Bruhn, Oliver, Marie Lindsay, Friederike Wiebel, et al. "Alternative Polyadenylation of ABC Transporters of the C-Family (ABCC1, ABCC2, ABCC3) and Implications on Posttranscriptional Micro-RNA Regulation." Molecular Pharmacology 97, no. 2 (2019): 112–22. http://dx.doi.org/10.1124/mol.119.116590.

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Vendrell, JA, F. Magnino, E. Danis, et al. "Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation." Journal of Molecular Endocrinology 32, no. 2 (2004): 397–414. http://dx.doi.org/10.1677/jme.0.0320397.

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We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.

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van Waterschoot, R. A. B., R. M. Eman, E. Wagenaar, et al. "ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity." Clinical Cancer Research 15, no. 24 (2009): 7616–23. http://dx.doi.org/10.1158/1078-0432.ccr-09-2127.

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Bruckmueller, Henrike, and Ingolf Cascorbi. "ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?" Expert Opinion on Drug Metabolism & Toxicology 17, no. 4 (2021): 369–96. http://dx.doi.org/10.1080/17425255.2021.1876661.

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Gökirmak, Tufan, Joseph P. Campanale, Adam M. Reitzel, Lauren E. Shipp, Gary W. Moy, and Amro Hamdoun. "Functional diversification of sea urchin ABCC1 (MRP1) by alternative splicing." American Journal of Physiology-Cell Physiology 310, no. 11 (2016): C911—C920. http://dx.doi.org/10.1152/ajpcell.00029.2016.

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The multidrug resistance protein (MRP) family encodes a diverse repertoire of ATP-binding cassette (ABC) transporters with multiple roles in development, disease, and homeostasis. Understanding MRP evolution is central to unraveling their roles in these diverse processes. Sea urchins occupy an important phylogenetic position for understanding the evolution of vertebrate proteins and have been an important invertebrate model system for study of ABC transporters. We used phylogenetic analyses to examine the evolution of MRP transporters and functional approaches to identify functional forms of sea urchin MRP1 (also known as SpABCC1). SpABCC1, the only MRP homolog in sea urchins, is co-orthologous to human MRP1, MRP3, and MRP6 (ABCC1, ABCC3, and ABCC6) transporters. However, efflux assays revealed that alternative splicing of exon 22, a region critical for substrate interactions, could diversify functions of sea urchin MRP1. Phylogenetic comparisons also indicate that while MRP1, MRP3, and MRP6 transporters potentially arose from a single transporter in basal deuterostomes, alternative splicing appears to have been the major mode of functional diversification in invertebrates, while duplication may have served a more important role in vertebrates. These results provide a deeper understanding of the evolutionary origins of MRP transporters and the potential mechanisms used to diversify their functions in different groups of animals.

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Abraham, Ajay, Savitha Varatharajan, Sreeja Karathedath, et al. "ABC Transporter Expression in Acute Myeloid Leukemia: Association with in Vitro Cytotoxicity and Prognostic Markers." Blood 120, no. 21 (2012): 1438. http://dx.doi.org/10.1182/blood.v120.21.1438.1438.

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Abstract Abstract 1438 Combination chemotherapy in Acute Myeloid Leukemia (AML) can cure approximately 25% of patients but the majority is still non-responsive. Drug resistance and relapse are considered to be the major reasons for treatment failure. Though overexpression of ATP-Binding-Cassette (ABC) transporters including ABCB1 and ABCG2 have been shown associated with lower remission rates and survival in AML, the role of majority of ABC transporter genes are still unknown. Present study aims to determine the role of candidate ABC transporter RNA expression (that are shown to directly or indirectly influence sensitivity towards Cytarabine (Ara-C) or Daunorubicin (Dnr)), on in vitro cytotoxicity and the influence of prognostic markers (NPM, FLT3-ITD, AML-ETO, CBFB-MYH11 and CD34) on these transporter expression. 177 adult AML patients (median age: 43 years (16–74 years)) other than AML-M3 were included in this study. Total RNA was extracted from diagnostic bone marrow mononuclear cells and expression levels for each target gene (ABCB1, ABCB6, ABCB10, ABCA3, ABCA5, ABCA6, ABCC3, ABCC11 and ABCG2) relative to housekeeping gene GAPDH was analyzed using Taqman based gene expression assays. ABCB6 and ABCC3 assays were custom designed and were normalized to ABL as housekeeping gene. The dCT values (where dCT = CT value of target gene – CT value of housekeeping gene; lower dCT corresponds to higher expression and vice versa) were used for comparing expression between groups. In vitro cytotoxicity was assessed using MTT cell viability assay and IC-50 was calculated. Based on Ara-C and Dnr IC50, these samples were categorized as sensitive or resistant (IC50 <5.2uM and >5.2 uM for Ara-C; <0.5uM and >0.5uM for Dnr). FLT3-ITD and NPM mutation status at diagnosis were determined by PCR followed by Genescan analysis using genomic DNA samples. AML-ETO and CBFB-MYH11 status were determined by RT-PCR. Wide variation in ABC transporter RNA expression was seen among AML patients (Fig 1a). Both ABCC3 and ABCB6 RNA expression were significantly higher (median ABCC3 dCT= 7.68 (−1.80–15.97) vs 10.62 (−0.66– 17.77); p= 0.0005; median ABCB6 dCT= 5.0 (−0.28 – 8.25) vs 5.4 (1.76 – 12.17); p=0.03)) in Dnr resistant patients (n=65) when compared to those who are sensitive to Dnr (n=53) (Fig 1b). No association was seen between any of these transporter expression and Ara-C in vitro cytotoxicity. Effects of NPM and FLT3 mutation status on ABC transporter genes were then evaluated. ABCB1 expression was significantly lower and ABCA5 expression was higher in patients with NPM mutation (n=50) when compared to those without mutation (n=126)-Table1. Patients with FLT3-ITD mutation (n=26) had a significantly lower ABCB1 expression when compared to those without mutation (n=150)-Table1. Low ABCB1 in this group could probably be due to the fact that NPM mutation was also positive in 16 out of 26 FlT3-ITD mutated patients. ABCB6 expression was significantly lower in FLT3-ITD positive patients (Table1). Other mitochondrial transporters like ABCG2 and ABCB10 showed a trend to low expression in FLT3-ITD patients when compared to those without FLT3 mutation (p=0.06 and p=0.1 respectively, Table1). Eighteen patients were positive for AML-ETO (n=12) or CBFB-MYH11 (n=6) and the RNA expression of ABCA5, ABCA3 and ABCG2 were significantly lower in this group compared to those who were negative for AML-ETO or CBFB-MYH11 (Table1). In addition, ABCB1 and ABCG2 expression was significantly higher in CD34 positive patients (CD34 >20% as analysed by flow cytometry) when compared to those with low CD34 expression (Table1) This study has come up with previously unrecognized aspects in ABC transporter expression and its role in AML. Low expression of ABCB1, a well accepted candidate for drug resistance, in NPM mutated AML could be one of the reasons which make NPM mutation a favourable prognostic marker. ABCC3 and ABCB6 which have shown association with Dnr sensitivity in this study could be a key avenue for further investigation. This comprehensive analysis on ABC transporter expression and its association with in vitro cytotoxicity and prognostic markers suggests ABCC3, ABCB6 and ABCA5 as probable targets which can be modulated for improving chemotherapeutic responses. Disclosures: No relevant conflicts of interest to declare.

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Wang, Zhan, Qingyu Zhou, Gary D. Kruh, and James M. Gallo. "Dose-Dependent Disposition of Methotrexate in Abcc2 and Abcc3 Gene Knockout Murine Models." Drug Metabolism and Disposition 39, no. 11 (2011): 2155–61. http://dx.doi.org/10.1124/dmd.111.041228.

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Lagas, J. S., L. Fan, E. Wagenaar, et al. "P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide." Clinical Cancer Research 16, no. 1 (2009): 130–40. http://dx.doi.org/10.1158/1078-0432.ccr-09-1321.

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van der Kolk, Dorina M., Susan D. P. W. M. Peeters, Gerald de Haan, Leonid Bystrykh, Elisabeth G. E. de Vries, and Edo Vellenga. "Selective Expression of a Number of ABC Transporter Genes in Normal CD34+CD38− Versus CD34+CD38− Cells, with a Reverse Pattern in a Subgroup of AML Patients." Blood 104, no. 11 (2004): 4291. http://dx.doi.org/10.1182/blood.v104.11.4291.4291.

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Abstract Several ABC transporters involved in drug transport have been identified in hematopoietic stem cells, including ABCB1, ABCC1 and ABCG2. The ABC transporters play a role in chemotherapy resistant AML, although the relevant information is mostly obtained from the total AML cell population instead of the leukemic stem cells characterized by the CD34+CD38− phenotype. In this study we investigated which ABC transporters are selectively expressed in normal CD34+CD38− hematopoietic stem cells versus CD34+CD38+ cells, and to what extent lineage-restricted modulation is aberrantly regulated in AML stem cells. We first investigated murine microarray expression data of 29 ABC transporter genes in lin−sca-1+c-kit+ cells (available on www.webqtl.org). Based on these data 7 of the 29 ABC transporters were selected with a high expression profile (abcg1, abcb2, abca2, abcd1, abcc3, abcc5, and abcg2). Based on data published at www.sciencemag.org/cgi/content/full/1073823/DC1, concerning the lineage restricted expression of genes in lin−AA4.1+ + c-kit+sca-1+ murine stem cells, 6 additional stem cell-related ABC transporters (abcb1, abcb11, abcc1b, abcd4, abce1 and abcf2) were selected. The mRNA expression of the 13 ABC transporters was analyzed in the CD34+CD38− versus CD34+CD38+ fraction of human normal bone marrow cells (n=10) by quantitative RT-PCR. Five ABC transporter genes were not detectable in the human CD34+CD38− and CD34+CD38+cells (ABCA2, ABCB11, ABCC3, ABCD1 and ABCF2). Three ABC transporters were expressed equally in both fractions (ABCC5, ABCE1 and ABCG2). However, five ABC transporters were differentially expressed, with a higher expression in the CD34+CD38− cells, (ABCB1, ratio of CD34+CD38+/CD34+CD38− expression of 0.22, p<0.001; ABCG1, 0.27, p<0.001; ABCC1, 0.52, p<0.001; ABCD4, 0.60, p<0.001; and ABCB2, 0.71, p<0.02). Additionally these five ABC transporters were studied in sorted AML subpopulations (n=7). In the sorted AML cells (CD34+CD38− versus CD34+CD38+) a more heterogeneous expression pattern was observed as compared to normal CD34+CD38− cells. In general, the expression levels of ABCB1 and ABCC1 in the AML subpopulations were lower than in normal CD34+CD38− cells, ABCB2 expression was higher in the AML fractions and ABCG1 and ABCD4 were expressed similar in AML and normal CD34+CD38− cells. Downregulation of the ABC transporters in the leukemic CD34+CD38+ cells was observed in 50%–60% of the samples, the reverse pattern was observed for the remaining cases, independent of FAB classification. Since ABCG1 plays a prominent role in cholesterol transport and was strongly downregulated in normal CD34+CD38+ cells (ratio 0.27, p<0.001), the mRNA expression of a number of additional cholesterol synthesis genes was investigated. PPARβ, LXRα and HMCGCoA reductase appeared to be downregulated in the CD34+CD38+ cells (ratios of 0.59, p=0.002, 0.32, p<0.001 and 0.59, p= 0.002 respectively). In conclusion, these results indicate that cholesterol synthesis and transport might play an important role in hematopoietic stem cells. Furthermore, a number of ABC transporter genes appeared to be predominantly expressed in hematopoietic stem cells, and are downregulated upon maturation, whereas the reverse pattern is observed in about 40% of the AML patients suggesting that these more committed leukemic cells might have gained some properties of the leukemic stem cells.

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Seborova, Karolina, Alzbeta Kloudova-Spalenkova, Kamila Koucka, et al. "The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes." International Journal of Molecular Sciences 23, no. 1 (2021): 73. http://dx.doi.org/10.3390/ijms23010073.

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The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

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Abualsunun, Walaa Ali, and Micheline Piquette-Miller. "STAT3 is involved in IL-6-Mediated Downregulation of Hepatic Transporters in Mice." Journal of Pharmacy & Pharmaceutical Sciences 21, no. 1s (2018): 325s—334s. http://dx.doi.org/10.18433/jpps30241.

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Interleukin (IL)-6 decreases hepatic expression of numerous transporters. Although IL-6 signaling occurs through STAT3, the extent of the involvement of the STAT3 signaling pathway has not been elucidated. PURPOSE: Our objective was to investigate whether IL-6-mediated effects occur through STAT3, and whether PXR plays a role in this regulation. METHOD: PXR null (-/-) or wild-type (+/+) male mice were pre-dosed with a selective STAT3 inhibitor S3I-201 (7.5 mg/kg ip) or vehicle (n=5-8/group) 30 minutes before receiving a single dose of IL-6 (1 µg ip) or saline. Animals were sacrificed after 6 hours and liver samples were analyzed using qRT-PCR and western blotting. RESULTS: As compared to saline controls, IL-6 decreased the expression of Cyp3a, Abcb1a, Abcc3, and Slco1a4 20-70% similarly in PXR (+/+) and (-/-) mice at 6 hr, while downregulation of Abcb11, Abcc2, Slc10a1and Slco2b1 was only seen in PXR (+/+). Pre-administration of S3I-201 attenuated IL-6-mediated changes of most transporters in PXR (+/+) and PXR (-/-) mice. At early times after IL-6 administration (10-120 minutes), transcript levels of Socs3, PXR, Abcb1a, Abcc3, Abcb11, Slco1a4 and Slco2b1were increased in PXR (+/+) mice. CONCLUSIONS: Our findings demonstrate that IL-6 imposes a significant downregulation of numerous ABC and SLC transporters in liver primarily through activation of the STAT3 signaling pathway. Based on time-dependent changes in transporter expression, downregulation likely occurs downstream of STAT3 activation. As IL-6 is elevated in many diseases, understanding the underlying mechanism(s) involved in transporter dysregulation will allow us to predict potential drug-disease interactions.

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Vasilyeva, Aksana, Selvi Durmus, Lie Li, et al. "Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b." Cancer Research 75, no. 13 (2015): 2729–36. http://dx.doi.org/10.1158/0008-5472.can-15-0280.

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van der Schoor, Lori WE, Henkjan J. Verkade, Folkert Kuipers, and Johan W. Jonker. "New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition." Expert Opinion on Drug Metabolism & Toxicology 11, no. 2 (2014): 273–93. http://dx.doi.org/10.1517/17425255.2015.981152.

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Obonaga, Ricardo, Olga Lucía Fernández, Liliana Valderrama, et al. "Treatment Failure and Miltefosine Susceptibility in Dermal Leishmaniasis Caused by Leishmania Subgenus Viannia Species." Antimicrobial Agents and Chemotherapy 58, no. 1 (2013): 144–52. http://dx.doi.org/10.1128/aac.01023-13.

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ABSTRACTTreatment failure and parasite drug susceptibility in dermal leishmaniasis caused byLeishmania(Viannia) species are poorly understood. Prospective evaluation of drug susceptibility of strains isolated from individual patients before drug exposure and at clinical failure allows intrinsic and acquired differences in susceptibility to be discerned and analyzed. To determine whether intrinsic susceptibility or loss of susceptibility to miltefosine contributed to treatment failure, we evaluated the miltefosine susceptibility of intracellular amastigotes and promastigotes of sixLeishmania(Viannia)braziliensisand sixLeishmania(Viannia)panamensisstrains isolated sequentially, at diagnosis and treatment failure, from two children and four adults ≥55 years old with concurrent conditions. Four patients presented only cutaneous lesions, one had mucosal disease, and one had disseminated mucocutaneous disease. Expression of theLeishmaniadrug transporter genesabca2,abca3,abcc2,abcc3,abcg4,abcg6, andLbMTwas evaluated by quantitative reverse transcription-PCR (qRT-PCR). Intracellular amastigotes (median 50% effective concentration [EC50], 10.7 μmol/liter) were more susceptible to miltefosine than promastigotes (median EC50, 55.3 μmol/liter) (P< 0.0001). Loss of susceptibility at failure, demonstrated by a miltefosine EC50of >32 μmol/liter (the upper limit of intracellular amastigote assay), occurred inL. panamensisinfection in a child and inL. braziliensisinfection in an adult and was accompanied by decreased expression of the miltefosine transporter LbMT (LbMT/β-tubulin, 0.42- to 0.26-fold [P= 0.039] and 0.70- to 0.57-fold [P= 0.009], respectively). LbMT gene polymorphisms were not associated with susceptibility phenotype.LeishmaniaABCA3 transporter expression was inversely correlated with miltefosine susceptibility (r= −0.605;P= 0.037). Loss of susceptibility is one of multiple factors involved in failure of miltefosine treatment in dermal leishmaniasis.

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Steinbach, Daniel, Jean-Pierre Gillet, Axel Sauerbrey, et al. "Expression Profiling of ABC-Transporters in Childhood AML Reveals ABCA3 as a Potential Cause of Drug Resistance." Blood 104, no. 11 (2004): 1177. http://dx.doi.org/10.1182/blood.v104.11.1177.1177.

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Abstract A major issue in the treatment of acute myeloid leukemia (AML) is the development of resistance to chemotherapeutic drugs. While more than 80% of children with AML may initially achieve complete remission with current therapeutic regimens, a large number of these patients relapse with resistant disease; even with aggressive therapy, the event free survival rate is only about 50%. Several mechanisms of drug resistance have been identified. One of these is the overexpression of ATP-binding-cassette (ABC)-transporters that function as drug efflux pumps. The best characterized member of this family is the P-glycoprotein (P-gp or MDR1 or ABCB1), which is an important cause of drug resistance in adult AML but not in children with AML. We could recently show that the multidrug resistance-associated protein 3 (MRP3 or ABCC3) and the breast cancer resistance protein (BCRP or ABCG2) are associated with a poor response to therapy in childhood AML. The aim of the present study was to identify other members of this family of proteins which are involved in drug resistance. We were particularly interested in ABC-transporters which were overexpressed in AML samples compared to healthy bone marrow because this might be an important prerequisite for using such proteins as therapeutic targets. A new microarray (DualChip human ABC) was developed for the simultaneous detection and quantification of 38 ABC transporter genes. Samples from 30 children with AML were analyzed with this microarray and the results were compared with normal bone marrow. The expression of five genes (ABCA2, ABCA3, ABCB2, ABCC1, and ABCC10) which were overexpressed in most patient samples was then analyzed by real time PCR in 40 selected samples from children with previously untreated AML. Half of the patients had achieved complete remission after the first course of chemotherapy. The other 20 patients had also undergone the full induction therapy but had failed to achieve remission at this stage. Only the expression of ABCA3 was significantly higher (p=0.015) in patients with a poor response to therapy. There was a 4-fold difference between the median expressions in both groups. The expression of ABCA3 was not significantly associated with the expression of P-gp, MRP3 or BCRP. Our results show that ABCA3 is overexpressed in childhood AML compared to healthy bone marrow and that the expression of ABCA3 is associated with a poor response to therapy. Interestingly, there are two ways in which ABCA3 might influence the prognosis of AML. Like other ABC-transporters, it could be involved in drug efflux. On the other hand, it was recently shown that ABCA3 plays a role in apoptosis and that many cancer cell lines show amplifications of the ABCA3 gene. Further studies are warranted to analyze the clinical and biological relevance of ABCA3 in leukemia.

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Keppler, Dietrich. "Progress in the Molecular Characterization of Hepatobiliary Transporters." Digestive Diseases 35, no. 3 (2017): 197–202. http://dx.doi.org/10.1159/000450911.

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Over the last 25 years, our understanding of the driving forces for hepatobiliary elimination and knowledge of the molecular basis of uptake and efflux transport in hepatocytes have undergone fundamental changes. This refers to bile acids and many other endogenous substances as well as to drugs that are eliminated on the hepatobiliary route. In this development, not only molecular cloning, functional characterization, and localization of transporters were decisive, but also the discovery of hereditary mutations in genes encoding sinusoidal uptake transporters and canalicular export pumps in humans and rodents. Uptake by passive diffusion and elimination into bile driven by the electrochemical gradient are no longer considered relevant for hepatobiliary elimination in the intact organism. Furthermore, insights into the relative roles of uptake transporters and unidirectional ATP-driven efflux pumps were obtained when we established double-transfected polarized cell lines stably expressing, as an example, the hepatocellular uptake transporter OATP1B3 and the apical (canalicular) efflux pump multidrug resistance protein 2 (MRP2; ABCC2). ATP-dependent efflux transporters localized to the basolateral (sinusoidal) hepatocyte membrane, particularly MRP3 (ABCC3) and MRP4 (ABCC4), pump substances from hepatocytes into sinusoidal blood. Bile acids are substrates for human MRP4 in the presence of physiological concentrations of reduced glutathione, which undergoes co-transport. These efflux pumps have been recognized in recent years to play an important compensatory role in cholestasis and to contribute to the balance between uptake and efflux of bile acids and other organic anions during the vectorial transport from blood into bile. This sinusoidal efflux not only enables subsequent renal elimination but also facilitates the re-uptake of substances into neighboring hepatocytes located more centrally and downstream in the sinusoid.

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Lapczuk-Romanska, Joanna, Diana Busch, Ewa Gieruszczak, et al. "Membrane Transporters in Human Parotid Gland-Targeted Proteomics Approach." International Journal of Molecular Sciences 20, no. 19 (2019): 4825. http://dx.doi.org/10.3390/ijms20194825.

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Salivary glands provide secretory functions, including secretion of xenobiotics and among them drugs. However, there is no published information about protein abundance of drug transporters measured using reliable protein quantification methods. Therefore, mRNA expression and absolute protein content of clinically relevant ABC (n = 6) and SLC (n = 15) family member transporters in the human parotid gland, using the qRT-PCR and liquid chromatography‒tandem mass spectrometry (LC−MS/MS) method, were studied. The abundance of nearly all measured proteins ranged between 0.04 and 0.45 pmol/mg (OCT3 > MRP1 > PEPT2 > MRP4 > MATE1 > BCRP). mRNAs of ABCB1, ABCC2, ABCC3, SLC10A1, SLC10A2, SLC22A1, SLC22A5, SLC22A6, SLC22A7, SLC22A8, SLCO1A2, SLCO1B1, SLCO1B3 and SLCO2B1 were not detected. The present study provides, for the first time, information about the protein abundance of membrane transporters in the human parotid gland, which could further be used to define salivary bidirectional transport (absorption and secretion) mechanisms of endogenous compounds and xenobiotics.

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Grant, Caroline E., Mian Gao, Marianne K. DeGorter, Susan P. C. Cole, and Roger G. Deeley. "Structural Determinants of Substrate Specificity Differences between Human Multidrug Resistance Protein (MRP) 1 (ABCC1) and MRP3 (ABCC3)." Drug Metabolism and Disposition 36, no. 12 (2008): 2571–81. http://dx.doi.org/10.1124/dmd.108.022491.

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Fischer, Stephan, Mirko Pietsch, Kristin Schirmer, and Till Luckenbach. "Identification of multi-drug resistance associated proteins MRP1 (ABCC1) and MRP3 (ABCC3) from rainbow trout (Oncorhynchus mykiss)." Marine Environmental Research 69 (January 2010): S7—S10. http://dx.doi.org/10.1016/j.marenvres.2009.11.003.

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Ramsvik, Marie S., Bodil Bjørndal, Rita Vik, Inge Bruheim, Jon Skorve, and Rolf K. Berge. "Krill protein hydrolysate reduces plasma triacylglycerol level with concurrent increase in plasma bile acid level and hepatic fatty acid catabolism in high-fat fed mice." Functional Foods in Health and Disease 3, no. 11 (2013): 428. http://dx.doi.org/10.31989/ffhd.v3i11.34.

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Background: Krill powder, consisting of both lipids and proteins, has been reported to modulate hepatic lipid catabolism in animals. Fish protein hydrolysate diets have also been reported to affect lipid metabolism and to elevate bile acid (BA) level in plasma. BA interacts with a number of nuclear receptors and thus affects a variety of signaling pathways, including very low density lipoprotein (VLDL) secretion. The aim of the present study was to investigate whether a krill protein hydrolysate (KPH) could affect lipid and BA metabolism in mice. Method: C57BL/6 mice were fed a high-fat (21%, w/w) diet containing 20% crude protein (w/w) as casein (control group) or KPH for 6 weeks. Lipids and fatty acid composition were measured from plasma, enzyme activity and gene expression were analyzed from liver samples, and BA was measured from plasma.Results: The effect of dietary treatment with KPH resulted in reduced levels of plasma triacylglycerols (TAG) and non-esterified fatty acids (NEFAs). The KPH treated mice had also a marked increased plasma BA concentration. The increased plasma BA level was associated with induction of genes related to membrane canalicular exporter proteins (Abcc2, Abcb4) and to BA exporters to blood (Abcc3 and Abcc4). Of note, we observed a 2-fold increased nuclear farnesoid X receptor (Fxr) mRNA levels in the liver of mice fed KPH. We also observed increased activity of the nuclear peroxiosme proliferator-activated receptor alpha (PPARα) target gene carnitine plamitoyltransferase 2 (CPT-2). Conclusion: The KPH diet showed to influence lipid and BA metabolism in high-fat fed mice. Moreover, increased mitochondrial fatty acid oxidation and elevation of BA concentration may regulate the plasma level of TAGs and NEFAs.Key words: Krill protein hydrolysate, triacylglycerol, fatty acids, TNFα

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Lukanov, Tsvetelin, Milena Ivanova, Petya Yankova, et al. "Impact of CYP3A7, CYP2D6 and ABCC2/ABCC3 polymorphisms on tacrolimus steady state concentrations in Bulgarian kidney transplant recipients." Biotechnology & Biotechnological Equipment 36, no. 1 (2022): 362–69. http://dx.doi.org/10.1080/13102818.2022.2081517.

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Martino, A., D. Campa, G. Buda, et al. "Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and multiple myeloma risk: a case–control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium." Leukemia 26, no. 6 (2011): 1419–22. http://dx.doi.org/10.1038/leu.2011.352.

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Reyes-Avendaño, Itayetzi, Edilburga Reyes-Jiménez, Karina González-García, et al. "Quercetin Regulates Key Components of the Cellular Microenvironment during Early Hepatocarcinogenesis." Antioxidants 11, no. 2 (2022): 358. http://dx.doi.org/10.3390/antiox11020358.

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Hepatocellular carcinoma (HCC) is a health problem worldwide due to its high mortality rate, and the tumor microenvironment (TME) plays a key role in the HCC progression. The current ineffective therapies to fight the disease still warrant the development of preventive strategies. Quercetin has been shown to have different antitumor activities; however, its effect on TME components in preneoplastic lesions has not been fully investigated yet. Here, we aimed to evaluate the effect of quercetin (10 mg/kg) on TME components during the early stages of HCC progression induced in the rat. Histopathological and immunohistochemical analyses showed that quercetin decreases the size of preneoplastic lesions, glycogen and collagen accumulation, the expression of cancer stem cells and myofibroblasts markers, and that of the transporter ATP binding cassette subfamily C member 3 (ABCC3), a marker of HCC progression and multi-drug resistance. Our results strongly suggest that quercetin has the capability to reduce key components of TME, as well as the expression of ABCC3. Thus, quercetin can be an alternative treatment for inhibiting the growth of early HCC tumors.

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Teng, Shirley, Veronika Jekerle, and Micheline Piquette-Miller. "INDUCTION OF ABCC3 (MRP3) BY PREGNANE X RECEPTOR ACTIVATORS." Drug Metabolism and Disposition 31, no. 11 (2003): 1296–99. http://dx.doi.org/10.1124/dmd.31.11.1296.

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Bruhn, Oliver, and Ingolf Cascorbi. "Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance." Expert Opinion on Drug Metabolism & Toxicology 10, no. 10 (2014): 1337–54. http://dx.doi.org/10.1517/17425255.2014.952630.

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Martino, A., D. Campa, G. Buda, et al. "Erratum: Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and multiple myeloma risk: a case—control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium." Leukemia 27, no. 7 (2013): 1615–16. http://dx.doi.org/10.1038/leu.2013.146.

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Szeri, Flora, Valentina Corradi, Fatemeh Niaziorimi, et al. "Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model." International Journal of Molecular Sciences 22, no. 13 (2021): 6910. http://dx.doi.org/10.3390/ijms22136910.

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Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site.

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Kawai, Masaomi, Yukie Saegusa, Meilan Jin, et al. "Mechanistic Study on Hepatocarcinogenesis of Piperonyl Butoxide in Mice." Toxicologic Pathology 37, no. 6 (2009): 761–69. http://dx.doi.org/10.1177/0192623309344087.

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To clarify the mechanism of piperonyl butoxide (PBO)-induced hepatocarcinogenesis in mice, male mice were subjected to a two-thirds partial hepatectomy, N-diethylnitrosamine (DEN) initiation, and a diet containing 0.6% PBO for eight weeks. The incidence of γ-glutamyl transpeptidase (GGT)-positive foci and PCNA-positive cells was significantly increased in the DEN + PBO group compared with the DEN-alone group. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis showed up-regulation of genes related to metabolism, such as cytochrome P450 1A1 and 2B10, and metabolic stress, such as Por, Nqo1, Nrf2, abcc3, and abcc4. Early responsive genes downstream of mitogen-activated protein kinase (MAPK), such as c-fos, c-jun, c-myc, and activating transcription factor 3 ( ATF3), were also up-regulated in this group. Positive immunohistochemical staining for ATF3 was diffusely observed in nonproliferating hepatocytes of the DEN + PBO group, but altered foci were negative or weakly positive for ATF3. The nuclei of hepatocytes within ATF3-negative foci were positive for cyclin D. Thus PBO can induce oxidative stress, activate the MAPK pathway, and increase ATF3 transcript levels in hepatocytes outside the altered foci during the early stage of PBO-induced hepatocarcinogenesis in mice.

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Journal articles on the topic 'ABCC3'

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