Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR56QTT)

• DOT Name: Sodium/hydrogen exchanger 8 (SLC9A8)
• Synonyms: Na(+)/H(+) exchanger 8; NHE-8; Solute carrier family 9 member 8
• Gene Name: SLC9A8
• UniProt ID: SL9A8_HUMAN
• Pfam ID: PF00999
• Sequence:
  MGEKMAEEERFPNTTHEGFNVTLHTTLVVTTKLVLPTPGKPILPVQTGEQAQQEEQSSGM
  TIFFSLLVLAICIILVHLLIRYRLHFLPESVAVVSLGILMGAVIKIIEFKKLANWKEEEM
  FRPNMFFLLLLPPIIFESGYSLHKGNFFQNIGSITLFAVFGTAISAFVVGGGIYFLGQAD
  VISKLNMTDSFAFGSLISAVDPVATIAIFNALHVDPVLNMLVFGESILNDAVSIVLTNTA
  EGLTRKNMSDVSGWQTFLQALDYFLKMFFGSAALGTLTGLISALVLKHIDLRKTPSLEFG
  MMIIFAYLPYGLAEGISLSGIMAILFSGIVMSHYTHHNLSPVTQILMQQTLRTVAFLCET
  CVFAFLGLSIFSFPHKFEISFVIWCIVLVLFGRAVNIFPLSYLLNFFRDHKITPKMMFIM
  WFSGLRGAIPYALSLHLDLEPMEKRQLIGTTTIVIVLFTILLLGGSTMPLIRLMDIEDAK
  AHRRNKKDVNLSKTEKMGNTVESEHLSELTEEEYEAHYIRRQDLKGFVWLDAKYLNPFFT
  RRLTQEDLHHGRIQMKTLTNKWYEEVRQGPSGSEDDEQELL
• Function: Na(+)/H(+) antiporter. Mediates the electoneutral exchange of intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry. Acts as an Na(+)/H(+) exchanger in the trans-Golgi. Contributes to the regulation of pH regulation of Golgi apparatus, and consequently, in protein trafficking and endosomal morphology. In germ cells, plays a crucial role in acrosome biogenesis and sperm development, probably by playing a role in the fusion of the Golgi-derived vesicles that form the acrosomal cap. Can also be active at the cell surface of specialized cells. In the small intestine, at the cell membrane, plays a major physiological role in transepithelial absorption of Na(+) and regulates intracellular pH homeostasis of intestinal epithelial cells. Acts as an important regulator of mucosal integrity in the intestine and in the stomach, could mediate the pH fluctuation necessary for mucin exocytosis or assist membrane trafficking of other proteins. Plays a role in photoreceptor survival and in the maintenance of intracellular pH homeostasis in retinal pigment epithelium (RPE cells).
• Tissue Specificity: Ubiquitous. Strongly expressed in skeletal muscle and kidney . Detected throughout the entire gastrointestinal tract, with high expression detected in stomach, duodenum and ascending colon .
• Reactome Pathway: Sodium/Proton exchangers (R-HSA-425986)

Molecular Interaction Atlas (MIA) of This DOT

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 8 (SLC9A8) affects the uptake of 3-iodothyronamine.	[15]

11 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 8 (SLC9A8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/hydrogen exchanger 8 (SLC9A8).	[13]

3 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 Sodium/hydrogen exchanger 8 (SLC9A8).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sodium/hydrogen exchanger 8 (SLC9A8).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the acetylation of Sodium/hydrogen exchanger 8 (SLC9A8).	[14]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] 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.
• [5] 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.
• [6] 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.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] 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.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [13] 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.
• [14] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [15] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.