Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT00PCW3)

• DOT Name: Sodium/hydrogen exchanger 9 (SLC9A9)
• Synonyms: Na(+)/H(+) exchanger 9; NHE-9; Solute carrier family 9 member 9
• Gene Name: SLC9A9
• Related Disease:
  Autism spectrum disorder
  Autism, susceptibility to, 16
• UniProt ID: SL9A9_HUMAN
• Pfam ID: PF00999
• Sequence:
  MERQSRVMSEKDEYQFQHQGAVELLVFNFLLILTILTIWLFKNHRFRFLHETGGAMVYGL
  IMGLILRYATAPTDIESGTVYDCVKLTFSPSTLLVNITDQVYEYKYKREISQHNINPHQG
  NAILEKMTFDPEIFFNVLLPPIIFHAGYSLKKRHFFQNLGSILTYAFLGTAISCIVIGLI
  MYGFVKAMIHAGQLKNGDFHFTDCLFFGSLMSATDPVTVLAIFHELHVDPDLYTLLFGES
  VLNDAVAIVLTYSISIYSPKENPNAFDAAAFFQSVGNFLGIFAGSFAMGSAYAIITALLT
  KFTKLCEFPMLETGLFFLLSWSAFLSAEAAGLTGIVAVLFCGVTQAHYTYNNLSSDSKIR
  TKQLFEFMNFLAENVIFCYMGLALFTFQNHIFNALFILGAFLAIFVARACNIYPLSFLLN
  LGRKQKIPWNFQHMMMFSGLRGAIAFALAIRNTESQPKQMMFTTTLLLVFFTVWVFGGGT
  TPMLTWLQIRVGVDLDENLKEDPSSQHQEANNLDKNMTKAESARLFRMWYSFDHKYLKPI
  LTHSGPPLTTTLPEWCGPISRLLTSPQAYGEQLKEDDVECIVNQDELAINYQEQASSPCS
  PPARLGLDQKASPQTPGKENIYEGDLGLGGYELKLEQTLGQSQLN
• Function: Endosomal Na(+), K(+)/H(+) antiporter. Mediates the electroneutral exchange of endosomal luminal H(+) for a cytosolic Na(+) or K(+) (Probable). By facilitating proton efflux, SLC9A9 counteracts the acidity generated by vacuolar (V)-ATPase, thereby limiting luminal acidification. Regulates organellar pH and consequently, e.g., endosome maturation and endocytic trafficking of plasma membrane receptors and neurotransporters. Promotes the recycling of transferrin receptors back to the cell surface to facilitate additional iron uptake in the brain. Regulates synaptic transmission by regulating the luminal pH of axonal endosomes. Regulates phagosome lumenal pH, thus affecting phagosome maturation, and consequently, microbicidal activity in macrophages. Can also be active at the cell surface of specialized cells, e.g., in the inner ear hair bundles uses the high K(+) of the endolymph to regulate intracelular pH.
• Tissue Specificity: Ubiquitously expressed in all tissues tested. Expressed at highest levels in heart and skeletal muscle, followed by placenta, kidney, and liver. Expressed in the brain, in the medulla and spinal cord.
• Reactome Pathway:
  Defective SLC9A9 causes autism 16 (AUTS16) (R-HSA-5619052)
  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
Autism spectrum disorder	DISXK8NV	Disputed	Autosomal dominant	[1]
Autism, susceptibility to, 16	DISXQ4S7	Limited	Autosomal dominant	[2]

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 9 (SLC9A9) affects the uptake of 3-iodothyronamine.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sodium/hydrogen exchanger 9 (SLC9A9).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Sodium/hydrogen exchanger 9 (SLC9A9).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[4]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[13]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 decreases the expression of Sodium/hydrogen exchanger 9 (SLC9A9).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [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] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] 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.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.
• [15] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.