Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ7PFVT)

• DOT Name: Sodium/hydrogen exchanger 3 (SLC9A3)
• Synonyms: Na(+)/H(+) exchanger 3; NHE-3; Solute carrier family 9 member 3
• Gene Name: SLC9A3
• Related Disease:
  Congenital secretory sodium diarrhea 8
  Congenital sodium diarrhea
• UniProt ID: SL9A3_HUMAN
• PDB ID: 7X2U
• Pfam ID: PF00999
• Sequence:
  MWGLGARGPDRGLLLALALGGLARAGGVEVEPGGAHGESGGFQVVTFEWAHVQDPYVIAL
  WILVASLAKIGFHLSHKVTSVVPESALLIVLGLVLGGIVWAADHIASFTLTPTVFFFYLL
  PPIVLDAGYFMPNRLFFGNLGTILLYAVVGTVWNAATTGLSLYGVFLSGLMGDLQIGLLD
  FLLFGSLMAAVDPVAVLAVFEEVHVNEVLFIIVFGESLLNDAVTVVLYNVFESFVALGGD
  NVTGVDCVKGIVSFFVVSLGGTLVGVVFAFLLSLVTRFTKHVRIIEPGFVFIISYLSYLT
  SEMLSLSAILAITFCGICCQKYVKANISEQSATTVRYTMKMLASSAETIIFMFLGISAVN
  PFIWTWNTAFVLLTLVFISVYRAIGVVLQTWLLNRYRMVQLEPIDQVVLSYGGLRGAVAF
  ALVVLLDGDKVKEKNLFVSTTIIVVFFTVIFQGLTIKPLVQWLKVKRSEHREPRLNEKLH
  GRAFDHILSAIEDISGQIGHNYLRDKWSHFDRKFLSRVLMRRSAQKSRDRILNVFHELNL
  KDAISYVAEGERRGSLAFIRSPSTDNVVNVDFTPRSSTVEASVSYLLRENVSAVCLDMQS
  LEQRRRSIRDAEDMVTHHTLQQYLYKPRQEYKHLYSRHELTPTEDEKQDREIFHRTMRKR
  LESFKSTKLGLNQNKKAAKLYKRERAQKRRNSSIPNGKLPMESPAQNFTIKEKDLELSDT
  EEPPNYDEEMSGGIEFLASVTKDTASDSPAGIDNPVFSPDEALDRSLLARLPPWLSPGET
  VVPSQRARTQIPYSPGTFCRLMPFRLSSKSVDSFLQADGPEERPPAALPESTHM
• Function: Plasma membrane Na(+)/H(+) antiporter. Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, playing a key role in salt and fluid absorption and pH homeostasis. Major apical Na(+)/H(+) exchanger in kidney and intestine playing an important role in renal and intestine Na(+) absorption and blood pressure regulation.
• KEGG Pathway:
  Proximal tubule bicarbo.te reclamation (hsa04964)
  Protein digestion and absorption (hsa04974)
  Bile secretion (hsa04976)
  Mineral absorption (hsa04978)
• Reactome Pathway: Sodium/Proton exchangers (R-HSA-425986)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital secretory sodium diarrhea 8	DIS1C6JF	Strong	Autosomal recessive	[1]
Congenital sodium diarrhea	DISDXE72	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sodium/hydrogen exchanger 3 (SLC9A3).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium/hydrogen exchanger 3 (SLC9A3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium/hydrogen exchanger 3 (SLC9A3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sodium/hydrogen exchanger 3 (SLC9A3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Sodium/hydrogen exchanger 3 (SLC9A3).	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Sodium/hydrogen exchanger 3 (SLC9A3).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sodium/hydrogen exchanger 3 (SLC9A3).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Sodium/hydrogen exchanger 3 (SLC9A3).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sodium/hydrogen exchanger 3 (SLC9A3).	[9]

References

• [1] Application of Whole Exome Sequencing in Congenital Secretory Diarrhea Diagnosis. J Pediatr Gastroenterol Nutr. 2019 Jun;68(6):e106-e108. doi: 10.1097/MPG.0000000000002258.
• [2] Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum Mol Genet. 2015 Dec 1;24(23):6614-23. doi: 10.1093/hmg/ddv367. Epub 2015 Sep 10.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [6] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [7] Dexamethasone increases fluid absorption via Na+/H+ exchanger (NHE) 3 activation in normal human middle ear epithelial cells. Eur J Pharmacol. 2006 Apr 24;536(1-2):12-8. doi: 10.1016/j.ejphar.2006.02.031. Epub 2006 Feb 28.
• [8] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [9] Role of Na+/H+ exchanger in resveratrol-induced growth inhibition of human breast cancer cells. Med Oncol. 2012 Mar;29(1):25-32. doi: 10.1007/s12032-010-9786-7. Epub 2010 Dec 30.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.