Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0T78JI)

• DOT Name: Sodium/glucose cotransporter 1 (SLC5A1)
• Synonyms: Na(+)/glucose cotransporter 1; High affinity sodium-glucose cotransporter; Solute carrier family 5 member 1
• Gene Name: SLC5A1
• Related Disease: Glucose-galactose malabsorption
• UniProt ID: SC5A1_HUMAN
• PDB ID: 7SL8; 7SLA; 7WMV; 7YNI
• Pfam ID: PF00474
• Sequence:
  MDSSTWSPKTTAVTRPVETHELIRNAADISIIVIYFVVVMAVGLWAMFSTNRGTVGGFFL
  AGRSMVWWPIGASLFASNIGSGHFVGLAGTGAASGIAIGGFEWNALVLVVVLGWLFVPIY
  IKAGVVTMPEYLRKRFGGQRIQVYLSLLSLLLYIFTKISADIFSGAIFINLALGLNLYLA
  IFLLLAITALYTITGGLAAVIYTDTLQTVIMLVGSLILTGFAFHEVGGYDAFMEKYMKAI
  PTIVSDGNTTFQEKCYTPRADSFHIFRDPLTGDLPWPGFIFGMSILTLWYWCTDQVIVQR
  CLSAKNMSHVKGGCILCGYLKLMPMFIMVMPGMISRILYTEKIACVVPSECEKYCGTKVG
  CTNIAYPTLVVELMPNGLRGLMLSVMLASLMSSLTSIFNSASTLFTMDIYAKVRKRASEK
  ELMIAGRLFILVLIGISIAWVPIVQSAQSGQLFDYIQSITSYLGPPIAAVFLLAIFWKRV
  NEPGAFWGLILGLLIGISRMITEFAYGTGSCMEPSNCPTIICGVHYLYFAIILFAISFIT
  IVVISLLTKPIPDVHLYRLCWSLRNSKEERIDLDAEEENIQEGPKETIEIETQVPEKKKG
  IFRRAYDLFCGLEQHGAPKMTEEEEKAMKMKMTDTSEKPLWRTVLNVNGIILVTVAVFCH
  AYFA
• Function: Electrogenic Na(+)-coupled sugar simporter that actively transports D-glucose or D-galactose at the plasma membrane, with a Na(+) to sugar coupling ratio of 2:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump. Has a primary role in the transport of dietary monosaccharides from enterocytes to blood. Responsible for the absorption of D-glucose or D-galactose across the apical brush-border membrane of enterocytes, whereas basolateral exit is provided by GLUT2. Additionally, functions as a D-glucose sensor in enteroendocrine cells, triggering the secretion of the incretins GCG and GIP that control food intake and energy homeostasis. Together with SGLT2, functions in reabsorption of D-glucose from glomerular filtrate, playing a nonredundant role in the S3 segment of the proximal tubules. Transports D-glucose into endometrial epithelial cells, controlling glycogen synthesis and nutritional support for the embryo as well as the decidual transformation of endometrium prior to conception. Acts as a water channel enabling passive water transport across the plasma membrane in response to the osmotic gradient created upon sugar and Na(+) uptake. Has high water conductivity, comparable to aquaporins, and therefore is expected to play an important role in transepithelial water permeability, especially in the small intestine.
• Tissue Specificity: Expressed in intestine . Expressed in endometrial cells .
• KEGG Pathway:
  Carbohydrate digestion and absorption (hsa04973)
  Bile secretion (hsa04976)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Defective SLC5A1 causes congenital glucose/galactose malabsorption (GGM) (R-HSA-5656364)
  Intestinal hexose absorption (R-HSA-8981373)
  Cellular hexose transport (R-HSA-189200)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glucose-galactose malabsorption	DISBFXNW	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Sodium/glucose cotransporter 1 (SLC5A1) affects the uptake of Resveratrol.	[13]
CERC-801	DM3SZ7P	Phase 2	Sodium/glucose cotransporter 1 (SLC5A1) affects the transport of CERC-801.	[14]
D-glucose	DMMG2TO	Investigative	Sodium/glucose cotransporter 1 (SLC5A1) affects the transport of D-glucose.	[14]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phlorizin	DMNARGO	Investigative	Sodium/glucose cotransporter 1 (SLC5A1) affects the binding of Phlorizin.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[2]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[3]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[4]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[5]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[6]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[7]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	3,4-Dihydroxycinnamic Acid increases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sodium/glucose cotransporter 1 (SLC5A1).	[12]

1 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 decreases the methylation of Sodium/glucose cotransporter 1 (SLC5A1).	[9]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [5] 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.
• [6] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [7] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [8] Glucose absorption regulation and mechanism of the compounds in Lilium lancifolium Thunb on Caco-2?cells. Food Chem Toxicol. 2021 Mar;149:112010. doi: 10.1016/j.fct.2021.112010. Epub 2021 Jan 22.
• [9] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Synergistic action of the nephrotoxic mycotoxins ochratoxin A and citrinin at nanomolar concentrations in human proximal tubule-derived cells. Toxicol Lett. 2018 Jul;291:149-157. doi: 10.1016/j.toxlet.2018.04.014. Epub 2018 Apr 17.
• [13] Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. J Nutr Biochem. 2013 Nov;24(11):1823-9. doi: 10.1016/j.jnutbio.2013.04.003. Epub 2013 Aug 6.
• [14] Sodium-independent low-affinity D-glucose transport by human sodium/D-glucose cotransporter 1: critical role of tryptophan 561. Biochemistry. 2007 Mar 13;46(10):2758-66. doi: 10.1021/bi061696x. Epub 2007 Feb 9.
• [15] D-Glucose-recognition and phlorizin-binding sites in human sodium/D-glucose cotransporter 1 (hSGLT1): a tryptophan scanning study. Biochemistry. 2007 Nov 27;46(47):13616-28. doi: 10.1021/bi701193x. Epub 2007 Nov 6.