Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZVOY8T)

• DOT Name: Sodium/hydrogen exchanger 9B2 (SLC9B2)
• Synonyms: Na(+)/H(+) exchanger NHA2; Na(+)/H(+) exchanger-like domain-containing protein 2; NHE domain-containing protein 2; Sodium/hydrogen exchanger-like domain-containing protein 2; Solute carrier family 9 subfamily B member 2
• Gene Name: SLC9B2
• UniProt ID: SL9B2_HUMAN
• PDB ID: 7B4L; 7B4M
• Pfam ID: PF00999
• Sequence:
  MGDEDKRITYEDSEPSTGMNYTPSMHQEAQEETVMKLKGIDANEPTEGSILLKSSEKKLQ
  ETPTEANHVQRLRQMLACPPHGLLDRVITNVTIIVLLWAVVWSITGSECLPGGNLFGIII
  LFYCAIIGGKLLGLIKLPTLPPLPSLLGMLLAGFLIRNIPVINDNVQIKHKWSSSLRSIA
  LSIILVRAGLGLDSKALKKLKGVCVRLSMGPCIVEACTSALLAHYLLGLPWQWGFILGFV
  LGAVSPAVVVPSMLLLQGGGYGVEKGVPTLLMAAGSFDDILAITGFNTCLGIAFSTGSTV
  FNVLRGVLEVVIGVATGSVLGFFIQYFPSRDQDKLVCKRTFLVLGLSVLAVFSSVHFGFP
  GSGGLCTLVMAFLAGMGWTSEKAEVEKIIAVAWDIFQPLLFGLIGAEVSIASLRPETVGL
  CVATVGIAVLIRILTTFLMVCFAGFNLKEKIFISFAWLPKATVQAAIGSVALDTARSHGE
  KQLEDYGMDVLTVAFLSILITAPIGSLLIGLLGPRLLQKVEHQNKDEEVQGETSVQV
• Function: Electroneutral Na(+) Li(+)/H(+) antiporter that extrudes Na(+) or Li(+) in exchange for external protons across the membrane. Uses the proton gradient/membrane potential to extrude sodium. Contributes to the regulation of intracellular pH and sodium homeostasis. Also able to mediate Na(+)/Li(+) antiporter activity in kidney. May play a physiological role in renal tubular function and blood pressure homeostasis. Plays an important role for insulin secretion and clathrin-mediated endocytosis in beta-cells. Involved in sperm motility and fertility. It is controversial whether SLC9B2 plays a role in osteoclast differentiation or not.
• Tissue Specificity: Widely expressed . High levels detected in the distal tubules of the kidney nephron . Detected in red blood cells (at protein level) .
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

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
Sodium chloride	DMM3950	Approved	Sodium/hydrogen exchanger 9B2 (SLC9B2) affects the abundance of Sodium chloride.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[13]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[14]
Phloretin	DMYA50U	Investigative	Phloretin decreases the activity of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[15]

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 9B2 (SLC9B2).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sodium/hydrogen exchanger 9B2 (SLC9B2).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] 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.
• [11] 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.
• [12] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [15] A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18677-81. doi: 10.1073/pnas.0707120104. Epub 2007 Nov 13.