ABCC3 Membrane Protein Introduction

Introduction of ABCC3

ABCC3, also known as ATP-Binding Cassette, Subfamily C (CFTR/MRP), Member 3, CMOAT2, MOAT-D, MLP2, MRP3, or ABC31, is an approximately 169 kDa membrane transport protein that consists of 1527 amino acids. In humans, it is encoded by the ABCC3 gene located at the chromosome 17q21.33. ABCC3 belongs to the ATP-binding cassette (ABC) transporter family. ABC transporter is highly expressed in cancer cells where it effluxes a broad spectrum of anticancer drugs activity and thus contributes to multi-drug resistance (MDR). The ABCC3 protein shares 56% identity with the multidrug resistance-associated protein 1 (MRP1) and is 45% identical to the multidrug resistance-associated protein 1 (MRP2). And northern blot analysis displayed a high expression of 6.5-kb ABCC3 transcript in the liver, as well as a low expression in small intestine, colon, prostate, and pancreas.

Function of ABCC3 Membrane Protein

ABCC3 probably functions as an inducible transporter in the intestinal and biliary excretion of organic anions and serves as an alternative route for the export of glucuronides and bile acids from cholestatic hepatocytes. Its related pathways include pharmacokinetics pathway, vinca alkaloid pathway, and constitutive androstane receptor pathway. There are several diseases correlated with ABCC3 gene including extrahepatic cholestasis and Dubin-Johnson syndrome. ABCC3 is also a member of the ABCC family which has been implicated in drug resistance. In pancreatic cancer, 5-fluorouracil resistant capan1 cell line revealed some folds upregulation of ABCC1 and ABCC3 expression compared to the parental cell line. It is reported that ABCC3 is significantly expressed in hepatocellular biopsies and non-small cell lung cancer (NSCLC). It acts as a marker for MDR in NSCLC and is related to poor survivals. In other findings, overexpression of ABCC3 in glioblastoma multiforme is exhibited to be associated with high risk for death. Thus, ABCC3, together with ABCC1, may play as a prognostic factor in various carcinoma subsets.

Fig.1 Neighborhood of ABCC3 in pathway commons. (Cerami, 2011)

Application of ABCC3 Membrane Protein in Literature

1. Takechi T., et al. Interindividual differences in the expression of ATP-binding cassette and solute carrier family transporters in human skin: DNA methylation regulates transcriptional activity of the human ABCC3 gene. Drug Metab Dispos. 2018, 46(5): 628-635. PubMed ID: 29437875
   
   

   The report demonstrated a large inter-individual difference in the expression of drug transporters in human skin. CpG island (CGI) may act as an enhancer of the ABCC3 transcription and the methylation level of CGI contributed to the variability of ABCC3 expression in human skin.

2. Ghanem C.I. and Manautou J.E. Modulation of hepatic MRP3/ABCC3 by xenobiotics and pathophysiological conditions: role in drug pharmacokinetics. Curr Med Chem. 2018. PubMed ID: 29473496
   
   

   This review examined the changes in expression and regulation of the transporter MPR3/ABCC3 from basolateral hepato via xenobiotics under different pathophysiological conditions. They also focused on the results of such changes in the pharmacokinetic, pharmacodynamic and toxicity of diverse drugs transported by MRP3 in clinical application.

3. Li J., et al. FOXA transcriptional factor modulates insect susceptibility to Bacillus thuringiensis Cry1Ac toxin by regulating the expression of toxin-receptor ABCC2 and ABCC3 genes. Insect Biochem Mol Biol. 2017, 88: 1-11. PubMed ID: 28736301
   
   

   Cry toxins released by Bacillus thuringiensis are insecticidal proteins popularly used in insect control. The findings in this study manifested that FOXA upregulated the expression of Cry1Ac-toxin receptor, ABCC2 and ABCC3, and that lower FOXA levels were associated with the tolerance to Cry toxin in cell lines as well as in lepidopteran larvae.

4. Luchessi A.D., et al. ABCC3 polymorphisms and mRNA expression influence the concentration of a carboxylic acid metabolite in patients on clopidogrel and aspirin therapy. Basic Clin Pharmacol Toxicol. 2017, 120(5): 466-474. PubMed ID: 27862978
   
   

   The results suggested that the upregulation of ABCC3 mRNA level resulted in rising plasma CAM levels by MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism probably contributed to the gene expression. Consequently, ABCC3 may be an attracting biomarker for the response to clopidogrel.

5. Chidambaran V., et al. ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children. Pharmacogenomics J. 2017, 17(2): 162-169. PubMed ID: 26810133
   
   

   Respiratory depression (RD) was a serious side effect of morphine and harmful to effective analgesia. Remarkably, it was the first research to report associations of ABCC3 variants with opioid-related RD, and forming morphine metabolite in two independent surgical cohorts.

ABCC3 Preparation Options

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Reference

1. Cerami E G, et al. (2011). Pathway Commons, a web resource for biological pathway data. Nucleic Acids Res. 39(Database issue), D685-90.

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