Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5N47TC)

• DOT Name: Sodium/hydrogen exchanger 6 (SLC9A6)
• Synonyms: Na(+)/H(+) exchanger 6; NHE-6; Solute carrier family 9 member 6
• Gene Name: SLC9A6
• Related Disease: Christianson syndrome
• UniProt ID: SL9A6_HUMAN
• Pfam ID: PF00999
• Sequence:
  MARRGWRRAPLRRGVGSSPRARRLMRPLWLLLAVGVFDWAGASDGGGGEARAMDEEIVSE
  KQAEESHRQDSANLLIFILLLTLTILTIWLFKHRRARFLHETGLAMIYGLLVGLVLRYGI
  HVPSDVNNVTLSCEVQSSPTTLLVNVSGKFYEYMLKGEISSHELNNVQDNEMLRKVTFDP
  EVFFNILLPPIIFYAGYSLKRRHFFRNLGSILAYAFLGTAISCFVIGSIMYGCVTLMKVT
  GQLAGDFYFTDCLLFGAIVSATDPVTVLAIFHELQVDVELYALLFGESVLNDAVAIVLSS
  SIVAYQPAGDNSHTFDVTAMFKSIGIFLGIFSGSFAMGAATGVVTALVTKFTKLREFQLL
  ETGLFFLMSWSTFLLAEAWGFTGVVAVLFCGITQAHYTYNNLSTESQHRTKQLFELLNFL
  AENFIFSYMGLTLFTFQNHVFNPTFVVGAFVAIFLGRAANIYPLSLLLNLGRRSKIGSNF
  QHMMMFAGLRGAMAFALAIRDTATYARQMMFSTTLLIVFFTVWVFGGGTTAMLSCLHIRV
  GVDSDQEHLGVPENERRTTKAESAWLFRMWYNFDHNYLKPLLTHSGPPLTTTLPACCGPI
  ARCLTSPQAYENQEQLKDDDSDLILNDGDISLTYGDSTVNTEPATSSAPRRFMGNSSEDA
  LDRELAFGDHELVIRGTRLVLPMDDSEPPLNLLDNTRHGPA
• Function: Endosomal Na(+), K(+)/H(+) antiporter. Mediates the electroneutral exchange of endosomal luminal H(+) for a cytosolic Na(+) or K(+). By facilitating proton efflux, SLC9A6 counteracts the acidity generated by vacuolar (V)-ATPase, thereby limiting luminal acidification. Responsible for alkalizing and maintaining the endosomal pH, and consequently in, e.g., endosome maturation and trafficking of recycling endosomal cargo. Plays a critical role during neurodevelopment by regulating synaptic development and plasticity. Implicated in the maintenance of cell polarity in a manner that is dependent on its ability to modulate intravesicular pH. Regulates intracelular pH in some specialized cells, osteoclasts and stereocilia where this transporter localizes to the plasma membrane.
• Tissue Specificity: Ubiquitous. High expression in brain, skeletal muscle, and heart, but is also detected at lower levels in most other tissues.
• KEGG Pathway: Cardiac muscle contraction (hsa04260)
• Reactome Pathway:
  Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH) (R-HSA-5619092)
  Sodium/Proton exchangers (R-HSA-425986)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Christianson syndrome	DISG6Y6W	Definitive	X-linked	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Sodium/hydrogen exchanger 6 (SLC9A6) affects the uptake of 3-iodothyronamine.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[9]
Ketamine	DMT5HA4	Approved	Ketamine decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sodium/hydrogen exchanger 6 (SLC9A6).	[17]

2 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 affects the methylation of Sodium/hydrogen exchanger 6 (SLC9A6).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sodium/hydrogen exchanger 6 (SLC9A6).	[14]

References

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• [2] 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.
• [3] 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.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Ketamine promotes the amyloidogenic pathway by regulating endosomal pH. Toxicology. 2022 Apr 15;471:153163. doi: 10.1016/j.tox.2022.153163. Epub 2022 Apr 1.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.