Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6HNHFV)

• DOT Name: Sodium/hydrogen exchanger 1 (SLC9A1)
• Synonyms: APNH; Na(+)/H(+) antiporter, amiloride-sensitive; Na(+)/H(+) exchanger 1; NHE-1; Solute carrier family 9 member 1
• Gene Name: SLC9A1
• Related Disease: Lichtenstein-Knorr syndrome
• UniProt ID: SL9A1_HUMAN
• PDB ID: 1Y4E; 2BEC; 2E30; 2HTG; 2KBV; 2L0E; 2MDF; 2YGG; 6BJF; 6NUC; 6NUF; 6NUU; 6ZBI; 7DSV; 7DSW; 7DSX
• Pfam ID: PF00999 ; PF16644
• Sequence:
  MVLRSGICGLSPHRIFPSLLVVVALVGLLPVLRSHGLQLSPTASTIRSSEPPRERSIGDV
  TTAPPEVTPESRPVNHSVTDHGMKPRKAFPVLGIDYTHVRTPFEISLWILLACLMKIGFH
  VIPTISSIVPESCLLIVVGLLVGGLIKGVGETPPFLQSDVFFLFLLPPIILDAGYFLPLR
  QFTENLGTILIFAVVGTLWNAFFLGGLMYAVCLVGGEQINNIGLLDNLLFGSIISAVDPV
  AVLAVFEEIHINELLHILVFGESLLNDAVTVVLYHLFEEFANYEHVGIVDIFLGFLSFFV
  VALGGVLVGVVYGVIAAFTSRFTSHIRVIEPLFVFLYSYMAYLSAELFHLSGIMALIASG
  VVMRPYVEANISHKSHTTIKYFLKMWSSVSETLIFIFLGVSTVAGSHHWNWTFVISTLLF
  CLIARVLGVLGLTWFINKFRIVKLTPKDQFIIAYGGLRGAIAFSLGYLLDKKHFPMCDLF
  LTAIITVIFFTVFVQGMTIRPLVDLLAVKKKQETKRSINEEIHTQFLDHLLTGIEDICGH
  YGHHHWKDKLNRFNKKYVKKCLIAGERSKEPQLIAFYHKMEMKQAIELVESGGMGKIPSA
  VSTVSMQNIHPKSLPSERILPALSKDKEEEIRKILRNNLQKTRQRLRSYNRHTLVADPYE
  EAWNQMLLRRQKARQLEQKINNYLTVPAHKLDSPTMSRARIGSDPLAYEPKEDLPVITID
  PASPQSPESVDLVNEELKGKVLGLSRDPAKVAEEDEDDDGGIMMRSKETSSPGTDDVFTP
  APSDSPSSQRIQRCLSDPGPHPEPGEGEPFFPKGQ
• Function: Electroneutral Na(+) /H(+) antiporter that extrudes Na(+) in exchange for external protons driven by the inward sodium ion chemical gradient, protecting cells from acidification that occurs from metabolism. Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry. Plays a key role in maintening intracellular pH neutral and cell volume, and thus is important for cell growth, proliferation, migration and survival. In addition, can transport lithium Li(+) and functions also as a Na(+)/Li(+) antiporter. SLC9A1 also functions in membrane anchoring and organization of scaffolding complexes that coordinate signaling inputs.
• Tissue Specificity: Kidney and intestine.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Apelin sig.ling pathway (hsa04371)
  Regulation of actin cytoskeleton (hsa04810)
  Thyroid hormone sig.ling pathway (hsa04919)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  Sodium/Proton exchangers (R-HSA-425986)
  Hyaluronan uptake and degradation (R-HSA-2160916)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lichtenstein-Knorr syndrome	DIS7UYZJ	Strong	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
AMG 386	DMQJXL4	Phase 3	Sodium/hydrogen exchanger 1 (SLC9A1) affects the transport of AMG 386.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the activity of Sodium/hydrogen exchanger 1 (SLC9A1).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the activity of Sodium/hydrogen exchanger 1 (SLC9A1).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[18]
ENIPORIDE	DME7OCX	Discontinued in Phase 2	ENIPORIDE decreases the activity of Sodium/hydrogen exchanger 1 (SLC9A1).	[19]
CARIPORIDE	DMV2DY3	Discontinued in Phase 2	CARIPORIDE decreases the activity of Sodium/hydrogen exchanger 1 (SLC9A1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sodium/hydrogen exchanger 1 (SLC9A1).	[21]
Phloretin	DMYA50U	Investigative	Phloretin decreases the activity of Sodium/hydrogen exchanger 1 (SLC9A1).	[22]
5'-(N-ethyl-N-isopropyl)amiloride	DM3TPMO	Investigative	5'-(N-ethyl-N-isopropyl)amiloride decreases the activity of Sodium/hydrogen exchanger 1 (SLC9A1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium/hydrogen exchanger 1 (SLC9A1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium/hydrogen exchanger 1 (SLC9A1).	[17]

References

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• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [8] 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.
• [9] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferator-activated receptor gamma-independent mechanism in breast cancer-derived cell lines. Clin Cancer Res. 2004 Oct 15;10(20):7022-30. doi: 10.1158/1078-0432.CCR-04-0879.
• [13] Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clin Cancer Res. 2003 Jun;9(6):2366-73.
• [14] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] Zoniporide: a potent and highly selective inhibitor of human Na(+)/H(+) exchanger-1. Eur J Pharmacol. 2002 Sep 6;451(1):37-41. doi: 10.1016/s0014-2999(02)02193-3.
• [20] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Alternative splicing of NHE-1 mediates Na-Li countertransport and associates with activity rate. Diabetes. 2003 Jun;52(6):1511-8. doi: 10.2337/diabetes.52.6.1511.
• [23] Mutations of Arg440 and Gly455/Gly456 oppositely change pH sensing of Na+/H+ exchanger 1. J Biol Chem. 2003 Apr 4;278(14):11828-35. doi: 10.1074/jbc.M213243200. Epub 2003 Jan 30.