Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6FY2KA)

• DOT Name: Sodium/myo-inositol cotransporter (SLC5A3)
• Synonyms: Na(+)/myo-inositol cotransporter; Sodium/myo-inositol transporter 1; SMIT1; Solute carrier family 5 member 3
• Gene Name: SLC5A3
• UniProt ID: SC5A3_HUMAN
• Pfam ID: PF00474
• Sequence:
  MRAVLDTADIAIVALYFILVMCIGFFAMWKSNRSTVSGYFLAGRSMTWVAIGASLFVSNI
  GSEHFIGLAGSGAASGFAVGAWEFNALLLLQLLGWVFIPIYIRSGVYTMPEYLSKRFGGH
  RIQVYFAALSLILYIFTKLSVDLYSGALFIQESLGWNLYVSVILLIGMTALLTVTGGLVA
  VIYTDTLQALLMIIGALTLMIISIMEIGGFEEVKRRYMLASPDVTSILLTYNLSNTNSCN
  VSPKKEALKMLRNPTDEDVPWPGFILGQTPASVWYWCADQVIVQRVLAAKNIAHAKGSTL
  MAGFLKLLPMFIIVVPGMISRILFTDDIACINPEHCMLVCGSRAGCSNIAYPRLVMKLVP
  VGLRGLMMAVMIAALMSDLDSIFNSASTIFTLDVYKLIRKSASSRELMIVGRIFVAFMVV
  ISIAWVPIIVEMQGGQMYLYIQEVADYLTPPVAALFLLAIFWKRCNEQGAFYGGMAGFVL
  GAVRLILAFAYRAPECDQPDNRPGFIKDIHYMYVATGLFWVTGLITVIVSLLTPPPTKEQ
  IRTTTFWSKKNLVVKENCSPKEEPYKMQEKSILRCSENNETINHIIPNGKSEDSIKGLQP
  EDVNLLVTCREEGNPVASLGHSEAETPVDAYSNGQAALMGEKERKKETDDGGRYWKFIDW
  FCGFKSKSLSKRSLRDLMEEEAVCLQMLEETRQVKVILNIGLFAVCSLGIFMFVYFSL
• Function: Electrogenic Na(+)-coupled sugar symporter that actively transports myo-inositol and its stereoisomer scyllo-inositol across the plasma membrane, with a Na(+) to sugar coupling ratio of 2:1. Maintains myo-inositol concentration gradient that defines cell volume and fluid balance during osmotic stress, in particular in the fetoplacental unit and central nervous system. Forms coregulatory complexes with voltage-gated K(+) ion channels, allosterically altering ion selectivity, voltage dependence and gating kinetics of the channel. In turn, K(+) efflux through the channel forms a local electrical gradient that modulates electrogenic Na(+)-coupled myo-inositol influx through the transporter. Associates with KCNQ1-KCNE2 channel in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability. Associates with KCNQ2-KCNQ3 channel altering ion selectivity, increasing Na(+) and Cs(+) permeation relative to K(+) permeation. Provides myo-inositol precursor for biosynthesis of phosphoinositides such as PI(4,5)P2, thus indirectly affecting the activity of phosphoinositide-dependent ion channels and Ca(2+) signaling upon osmotic stress.
• Reactome Pathway: Inositol transporters (R-HSA-429593)

Molecular Interaction Atlas (MIA) of This DOT

1 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/myo-inositol cotransporter (SLC5A3).	[1]

23 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/myo-inositol cotransporter (SLC5A3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[13]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[15]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[16]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[18]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[23]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Sodium/myo-inositol cotransporter (SLC5A3).	[24]

References

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• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
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• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] 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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [20] 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.
• [21] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [22] 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.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
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