Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBL2W7R)

• DOT Name: Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2)
• Synonyms: Glucose transporter type 2, liver; GLUT-2
• Gene Name: SLC2A2
• Related Disease:
  Glycogen storage disease due to GLUT2 deficiency
  Neonatal diabetes mellitus
  Permanent neonatal diabetes mellitus
  Transient neonatal diabetes mellitus
• UniProt ID: GTR2_HUMAN
• Pfam ID: PF00083
• Sequence:
  MTEDKVTGTLVFTVITAVLGSFQFGYDIGVINAPQQVIISHYRHVLGVPLDDRKAINNYV
  INSTDELPTISYSMNPKPTPWAEEETVAAAQLITMLWSLSVSSFAVGGMTASFFGGWLGD
  TLGRIKAMLVANILSLVGALLMGFSKLGPSHILIIAGRSISGLYCGLISGLVPMYIGEIA
  PTALRGALGTFHQLAIVTGILISQIIGLEFILGNYDLWHILLGLSGVRAILQSLLLFFCP
  ESPRYLYIKLDEEVKAKQSLKRLRGYDDVTKDINEMRKEREEASSEQKVSIIQLFTNSSY
  RQPILVALMLHVAQQFSGINGIFYYSTSIFQTAGISKPVYATIGVGAVNMVFTAVSVFLV
  EKAGRRSLFLIGMSGMFVCAIFMSVGLVLLNKFSWMSYVSMIAIFLFVSFFEIGPGPIPW
  FMVAEFFSQGPRPAALAIAAFSNWTCNFIVALCFQYIADFCGPYVFFLFAGVLLAFTLFT
  FFKVPETKGKSFEEIAAEFQKKSGSAHRPKAAVEMKFLGATETV
• Function: Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose. Likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by the beta cells; may comprise part of the glucose-sensing mechanism of the beta cell. May also participate with the Na(+)/glucose cotransporter in the transcellular transport of glucose in the small intestine and kidney. Also able to mediate the transport of dehydroascorbate.
• Tissue Specificity: Liver, insulin-producing beta cell, small intestine and kidney.
• KEGG Pathway:
  Insulin secretion (hsa04911)
  Prolactin sig.ling pathway (hsa04917)
  Glucagon sig.ling pathway (hsa04922)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  Maturity onset diabetes of the young (hsa04950)
  Carbohydrate digestion and absorption (hsa04973)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Regulation of gene expression in beta cells (R-HSA-210745)
  Regulation of insulin secretion (R-HSA-422356)
  Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS) (R-HSA-5619098)
  Intestinal hexose absorption (R-HSA-8981373)
  Cellular hexose transport (R-HSA-189200)
• BioCyc Pathway: MetaCyc:ENSG00000163581-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glycogen storage disease due to GLUT2 deficiency	DISXRSZ1	Definitive	Autosomal recessive	[1]
Neonatal diabetes mellitus	DISFHF9K	Strong	Autosomal recessive	[2]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Autosomal recessive	[2]
Transient neonatal diabetes mellitus	DIST826V	Strong	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2-deoxyglucose	DMIAHVU	Approved	Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) increases the transport of 2-deoxyglucose.	[24]
Fructose	DM43AN2	Approved	Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) increases the transport of Fructose.	[25]
CERC-801	DM3SZ7P	Phase 2	Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) increases the transport of CERC-801.	[24]
Dehydroascorbic acid	DMKYQO4	Investigative	Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) increases the uptake of Dehydroascorbic acid.	[27]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Captopril	DM458UM	Approved	Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) increases the Adverse drug reaction ADR of Captopril.	[26]
Leptin	DM5LY1H	Investigative	Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) increases the Reproductive tract disorder ADR of Leptin.	[26]

23 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 Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[13]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[15]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	3,4-Dihydroxycinnamic Acid increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[17]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[19]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[20]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[21]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[22]
Phloretin	DMYA50U	Investigative	Phloretin decreases the expression of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal affects the localization of Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2).	[23]

References

• [1] Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet. 1997 Nov;17(3):324-6. doi: 10.1038/ng1197-324.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] In vitro study of transporters involved in intestinal absorption of inorganic arsenic. Chem Res Toxicol. 2012 Feb 20;25(2):446-53. doi: 10.1021/tx200491f. Epub 2012 Jan 26.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] The effect of folate status on the uptake of physiologically relevant compounds by Caco-2 cells. Eur J Pharmacol. 2010 Aug 25;640(1-3):29-37. doi: 10.1016/j.ejphar.2010.04.056. Epub 2010 May 11.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism. J Biol Chem. 2011 Feb 25;286(8):6049-60. doi: 10.1074/jbc.M110.176842. Epub 2010 Dec 16.
• [18] Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem Pharmacol. 2016 Jan 15;100:98-111.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] Transcriptional Regulation of Human Arylamine N-Acetyltransferase 2 Gene by Glucose and Insulin in Liver Cancer Cell Lines. Toxicol Sci. 2022 Nov 23;190(2):158-172. doi: 10.1093/toxsci/kfac103.
• [21] In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic -Cell Model. Int J Mol Sci. 2022 May 1;23(9):5040. doi: 10.3390/ijms23095040.
• [22] Enhanced GLUT2 gene expression in an oleic acid-induced in vitro fatty liver model. Hepatol Res. 2002 Jun;23(2):138-144. doi: 10.1016/s1386-6346(01)00172-3.
• [23] Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. J Agric Food Chem. 2012 Sep 12;60(36):9180-7. doi: 10.1021/jf302831d. Epub 2012 Aug 29.
• [24] Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors. Biochem J. 1993 Mar 15;290 ( Pt 3)(Pt 3):701-6. doi: 10.1042/bj2900701.
• [25] A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts as a critical determinant of their substrate selectivity. Mol Membr Biol. 2007 Sep-Dec;24(5-6):455-63. doi: 10.1080/09687680701298143.
• [26] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [27] Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8. J Biol Chem. 2013 Mar 29;288(13):9092-101. doi: 10.1074/jbc.M112.436790. Epub 2013 Feb 8.