Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61QQTL)

• DOT Name: Amiloride-sensitive sodium channel subunit beta (SCNN1B)
• Synonyms: Beta-NaCH; Epithelial Na(+) channel subunit beta; Beta-ENaC; ENaCB; Nonvoltage-gated sodium channel 1 subunit beta; SCNEB
• Gene Name: SCNN1B
• Related Disease:
  Advanced cancer
  Autosomal recessive pseudohypoaldosteronism type 1
  Bronchiectasis
  Bronchiectasis with or without elevated sweat chloride 1
  Cystic fibrosis
  Gastric cancer
  High blood pressure
  Idiopathic bronchiectasis
  Liddle syndrome 1
  Neoplasm
  Nephrotic syndrome
  Primary aldosteronism
  Renal cell carcinoma
  Stomach cancer
  Ulcerative colitis
  Bacterial infection
  Liddle syndrome
  Essential hypertension
  Pelger-Huet anomaly
  Pulmonary disease
• UniProt ID: SCNNB_HUMAN
• PDB ID: 6BQN; 6WTH
• Pfam ID: PF00858
• Sequence:
  MHVKKYLLKGLHRLQKGPGYTYKELLVWYCDNTNTHGPKRIICEGPKKKAMWFLLTLLFA
  ALVCWQWGIFIRTYLSWEVSVSLSVGFKTMDFPAVTICNASPFKYSKIKHLLKDLDELME
  AVLERILAPELSHANATRNLNFSIWNHTPLVLIDERNPHHPMVLDLFGDNHNGLTSSSAS
  EKICNAHGCKMAMRLCSLNRTQCTFRNFTSATQALTEWYILQATNIFAQVPQQELVEMSY
  PGEQMILACLFGAEPCNYRNFTSIFYPHYGNCYIFNWGMTEKALPSANPGTEFGLKLILD
  IGQEDYVPFLASTAGVRLMLHEQRSYPFIRDEGIYAMSGTETSIGVLVDKLQRMGEPYSP
  CTVNGSEVPVQNFYSDYNTTYSIQACLRSCFQDHMIRNCNCGHYLYPLPRGEKYCNNRDF
  PDWAHCYSDLQMSVAQRETCIGMCKESCNDTQYKMTISMADWPSEASEDWIFHVLSQERD
  QSTNITLSRKGIVKLNIYFQEFNYRTIEESAANNIVWLLSNLGGQFGFWMGGSVLCLIEF
  GEIIIDFVWITIIKLVALAKSLRQRRAQASYAGPPPTVAELVEAHTNFGFQPDTAPRSPN
  TGPYPSEQALPIPGTPPPNYDSLRLQPLDVIESDSEGDAI
• Function: Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.
• Tissue Specificity: Detected in placenta, lung and kidney . Expressed in kidney (at protein level) .
• KEGG Pathway:
  Taste transduction (hsa04742)
  Aldosterone-regulated sodium reabsorption (hsa04960)
• Reactome Pathway:
  Sensory perception of salty taste (R-HSA-9730628)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autosomal recessive pseudohypoaldosteronism type 1	DIS7WSWQ	Strong	Autosomal recessive	[2]
Bronchiectasis	DIS5MYEE	Strong	Biomarker	[3]
Bronchiectasis with or without elevated sweat chloride 1	DISEGPSB	Strong	Autosomal dominant	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[6]
Idiopathic bronchiectasis	DISZ7YNI	Strong	GermlineCausalMutation	[7]
Liddle syndrome 1	DISKZL6E	Strong	Autosomal dominant	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[9]
Primary aldosteronism	DISOEFNH	Strong	Genetic Variation	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Posttranslational Modification	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[12]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[13]
Liddle syndrome	DISY0X0N	Supportive	Autosomal dominant	[14]
Essential hypertension	DIS7WI98	Limited	Genetic Variation	[15]
Pelger-Huet anomaly	DISCW4OI	Limited	Genetic Variation	[16]
Pulmonary disease	DIS6060I	Limited	Biomarker	[17]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[20]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[21]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[22]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[23]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[24]
Aldosterone	DM9S2JW	Approved	Aldosterone increases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[27]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Amiloride-sensitive sodium channel subunit beta (SCNN1B).	[26]

References

• [1] Sodium Channel Subunit SCNN1B Suppresses Gastric Cancer Growth and Metastasis via GRP78 Degradation.Cancer Res. 2017 Apr 15;77(8):1968-1982. doi: 10.1158/0008-5472.CAN-16-1595. Epub 2017 Feb 15.
• [2] Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism. N Engl J Med. 1999 Jul 15;341(3):156-62. doi: 10.1056/NEJM199907153410304.
• [3] Extensive sequence analysis of CFTR, SCNN1A, SCNN1B, SCNN1G and SERPINA1 suggests an oligogenic basis for cystic fibrosis-like phenotypes.Clin Genet. 2014 Jul;86(1):91-5. doi: 10.1111/cge.12234. Epub 2013 Jul 28.
• [4] Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways. Histochem Cell Biol. 2012 Mar;137(3):339-53. doi: 10.1007/s00418-011-0904-1. Epub 2011 Dec 30.
• [5] SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum.J Cyst Fibros. 2019 Mar;18(2):244-250. doi: 10.1016/j.jcf.2018.06.002. Epub 2018 Jun 20.
• [6] DNA Methylation of Candidate Genes (ACE II, IFN-, AGTR 1, CKG, ADD1, SCNN1B and TLR2) in Essential Hypertension: A Systematic Review and Quantitative Evidence Synthesis.Int J Environ Res Public Health. 2019 Dec 1;16(23):4829. doi: 10.3390/ijerph16234829.
• [7] Recommendations for the classification of diseases as CFTR-related disorders.J Cyst Fibros. 2011 Jun;10 Suppl 2:S86-102. doi: 10.1016/S1569-1993(11)60014-3.
• [8] Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit. J Clin Endocrinol Metab. 2005 Jan;90(1):340-4. doi: 10.1210/jc.2004-1027. Epub 2004 Oct 13.
• [9] Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats.Am J Physiol Renal Physiol. 2004 May;286(5):F922-35. doi: 10.1152/ajprenal.00277.2003. Epub 2004 Jan 6.
• [10] Liddle syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of SCNN1B.Endocr Connect. 2018 Dec;7(12):1528-1534. doi: 10.1530/EC-18-0484.
• [11] Identification of novel epigenetic markers for clear cell renal cell carcinoma.J Urol. 2008 Sep;180(3):1126-30. doi: 10.1016/j.juro.2008.04.137. Epub 2008 Jul 18.
• [12] Cytokine-dependent transcriptional down-regulation of epithelial sodium channel in ulcerative colitis.Gastroenterology. 2004 Jun;126(7):1711-20. doi: 10.1053/j.gastro.2004.03.010.
• [13] Gene expression in whole lung and pulmonary macrophages reflects the dynamic pathology associated with airway surface dehydration.BMC Genomics. 2014 Sep 10;15(1):726. doi: 10.1186/1471-2164-15-726.
• [14] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [15] Association of SCNN1B promoter methylation with essential hypertension.Mol Med Rep. 2016 Dec;14(6):5422-5428. doi: 10.3892/mmr.2016.5905. Epub 2016 Oct 31.
• [16] Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC.J Steroid Biochem Mol Biol. 2010 Mar;119(1-2):84-8. doi: 10.1016/j.jsbmb.2010.01.002. Epub 2010 Jan 12.
• [17] Targeting of cathepsin S reduces cystic fibrosis-like lung disease.Eur Respir J. 2019 Mar 28;53(3):1801523. doi: 10.1183/13993003.01523-2018. Print 2019 Mar.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [20] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [21] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [22] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [23] Modification of biophysical properties of lung epithelial Na(+) channels by dexamethasone. Am J Physiol Cell Physiol. 2000 Sep;279(3):C762-70. doi: 10.1152/ajpcell.2000.279.3.C762.
• [24] P2Y receptor regulation of sodium transport in human mammary epithelial cells. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1472-80. doi: 10.1152/ajpcell.00068.2007. Epub 2007 Aug 22.
• [25] Epithelial sodium channel in a human trophoblast cell line (BeWo). J Membr Biol. 2008 Jun;223(3):127-39. doi: 10.1007/s00232-008-9119-3. Epub 2008 Jul 30.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.