Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU7E9G7)

• DOT Name: Sodium/iodide cotransporter (SLC5A5)
• Synonyms: Na(+)/I(-) cotransporter; Natrium iodide transporter; Sodium-iodide symporter; Na(+)/I(-) symporter; Solute carrier family 5 member 5
• Gene Name: SLC5A5
• Related Disease:
  Familial thyroid dyshormonogenesis 1
  Familial thyroid dyshormonogenesis
• UniProt ID: SC5A5_HUMAN
• Pfam ID: PF00474
• Sequence:
  MEAVETGERPTFGAWDYGVFALMLLVSTGIGLWVGLARGGQRSAEDFFTGGRRLAALPVG
  LSLSASFMSAVQVLGVPSEAYRYGLKFLWMCLGQLLNSVLTALLFMPVFYRLGLTSTYEY
  LEMRFSRAVRLCGTLQYIVATMLYTGIVIYAPALILNQVTGLDIWASLLSTGIICTFYTA
  VGGMKAVVWTDVFQVVVMLSGFWVVLARGVMLVGGPRQVLTLAQNHSRINLMDFNPDPRS
  RYTFWTFVVGGTLVWLSMYGVNQAQVQRYVACRTEKQAKLALLINQVGLFLIVSSAACCG
  IVMFVFYTDCDPLLLGRISAPDQYMPLLVLDIFEDLPGVPGLFLACAYSGTLSTASTSIN
  AMAAVTVEDLIKPRLRSLAPRKLVIISKGLSLIYGSACLTVAALSSLLGGGVLQGSFTVM
  GVISGPLLGAFILGMFLPACNTPGVLAGLGAGLALSLWVALGATLYPPSEQTMRVLPSSA
  ARCVALSVNASGLLDPALLPANDSSRAPSSGMDASRPALADSFYAISYLYYGALGTLTTV
  LCGALISCLTGPTKRSTLAPGLLWWDLARQTASVAPKEEVAILDDNLVKGPEELPTGNKK
  PPGFLPTNEDRLFFLGQKELEGAGSWTPCVGHDGGRDQQETNL
• Function: Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland. Can also mediate the transport of chlorate, thiocynate, nitrate and selenocynate.
• Tissue Specificity: Expression is primarily in thyroid tissue, but also to a lower extent in mammary gland and ovary. Expression is reduced in tumors.
• KEGG Pathway: Thyroid hormone synthesis (hsa04918)
• Reactome Pathway:
  Organic anion transporters (R-HSA-428643)
  Defective SLC5A5 causes thyroid dyshormonogenesis 1 (TDH1) (R-HSA-5619096)
  Thyroxine biosynthesis (R-HSA-209968)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial thyroid dyshormonogenesis 1	DISAXKZN	Definitive	Autosomal recessive	[1]
Familial thyroid dyshormonogenesis	DISALTXN	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
IODIDE	DM3FZ6P	Investigative	Sodium/iodide cotransporter (SLC5A5) increases the uptake of IODIDE.	[17]

21 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/iodide cotransporter (SLC5A5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium/iodide cotransporter (SLC5A5).	[4]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Sodium/iodide cotransporter (SLC5A5).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sodium/iodide cotransporter (SLC5A5).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Sodium/iodide cotransporter (SLC5A5).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sodium/iodide cotransporter (SLC5A5).	[8]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Sodium/iodide cotransporter (SLC5A5).	[3]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Sodium/iodide cotransporter (SLC5A5).	[3]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Sodium/iodide cotransporter (SLC5A5).	[9]
Romidepsin	DMT5GNL	Approved	Romidepsin increases the expression of Sodium/iodide cotransporter (SLC5A5).	[3]
Tazarotene	DM8SMD1	Approved	Tazarotene increases the expression of Sodium/iodide cotransporter (SLC5A5).	[3]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sodium/iodide cotransporter (SLC5A5).	[5]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sodium/iodide cotransporter (SLC5A5).	[5]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Sodium/iodide cotransporter (SLC5A5).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sodium/iodide cotransporter (SLC5A5).	[12]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Sodium/iodide cotransporter (SLC5A5).	[13]
PJ34	DMXO6YH	Preclinical	PJ34 increases the expression of Sodium/iodide cotransporter (SLC5A5).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium/iodide cotransporter (SLC5A5).	[3]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Sodium/iodide cotransporter (SLC5A5).	[3]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Sodium/iodide cotransporter (SLC5A5).	[15]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate decreases the expression of Sodium/iodide cotransporter (SLC5A5).	[16]

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 increases the methylation of Sodium/iodide cotransporter (SLC5A5).	[11]

References

• [1] Congenital hypothyroidism caused by defective iodide transport. J Pediatr. 1985 Jun;106(6):950-3. doi: 10.1016/s0022-3476(85)80249-3.
• [2] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [3] Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer. 2006 Sep;13(3):797-826. doi: 10.1677/erc.1.01143.
• [4] Multifaceted suppression of aggressive behavior of thyroid carcinoma by all-trans retinoic acid induced re-differentiation. Mol Cell Endocrinol. 2012 Jan 2;348(1):260-9. doi: 10.1016/j.mce.2011.09.002. Epub 2011 Sep 6.
• [5] Antiproliferation and redifferentiation in thyroid cancer cell lines by polyphenol phytochemicals. J Korean Med Sci. 2011 Jul;26(7):893-9. doi: 10.3346/jkms.2011.26.7.893. Epub 2011 Jun 20.
• [6] Robust Thyroid Gene Expression and Radioiodine Uptake Induced by Simultaneous Suppression of BRAF V600E and Histone Deacetylase in Thyroid Cancer Cells. J Clin Endocrinol Metab. 2016 Mar;101(3):962-71. doi: 10.1210/jc.2015-3433. Epub 2016 Jan 11.
• [7] Increased iodine uptake in thyroid carcinoma after treatment with sodium butyrate and decitabine (5-Aza-dC). Otolaryngol Head Neck Surg. 2007 Nov;137(5):722-8. doi: 10.1016/j.otohns.2007.07.030.
• [8] Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid. 2005 Mar;15(3):222-31. doi: 10.1089/thy.2005.15.222.
• [9] Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):81-8. doi: 10.1016/j.taap.2012.01.029. Epub 2012 Feb 8.
• [10] Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles. Thyroid. 2007 Dec;17(12):1189-200. doi: 10.1089/thy.2007.0215.
• [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] Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer. Biochem Biophys Res Commun. 2016 Jan 15;469(3):679-85. doi: 10.1016/j.bbrc.2015.12.008. Epub 2015 Dec 18.
• [13] Effects of theophylline on radioiodide uptake in MCF-7 breast cancer and NIS gene-transduced SNU-C5 colon cancer cells. Cancer Biother Radiopharm. 2009 Apr;24(2):201-8. doi: 10.1089/cbr.2008.0555.
• [14] The PARP inhibitor PJ34 modifies proliferation, NIS expression and epigenetic marks in thyroid cancer cell lines. Mol Cell Endocrinol. 2013 Jan 5;365(1):1-10. doi: 10.1016/j.mce.2012.08.019. Epub 2012 Sep 5.
• [15] Protein synthesis inhibitors, in synergy with 5-azacytidine, restore sodium/iodide symporter gene expression in human thyroid adenoma cell line, KAK-1, suggesting trans-active transcriptional repressor. J Clin Endocrinol Metab. 2007 Mar;92(3):1080-7. doi: 10.1210/jc.2006-2106. Epub 2006 Dec 12.
• [16] The promoter of the human sodium/iodide symporter responds to certain phthalate plasticisers. Mol Cell Endocrinol. 2005 Dec 1;244(1-2):75-8. doi: 10.1016/j.mce.2005.06.009. Epub 2005 Oct 28.
• [17] Visualization of endogenous p53-mediated transcription in vivo using sodium iodide symporter. Clin Cancer Res. 2005 Jan 1;11(1):123-8.