Details of Drug Off-Target (DOT)

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

• DOT Name: Sodium-dependent noradrenaline transporter (SLC6A2)
• Synonyms: Norepinephrine transporter; NET; Solute carrier family 6 member 2
• Gene Name: SLC6A2
• Related Disease: Postural orthostatic tachycardia syndrome
• UniProt ID: SC6A2_HUMAN
• Pfam ID: PF00209
• Sequence:
  MLLARMNPQVQPENNGADTGPEQPLRARKTAELLVVKERNGVQCLLAPRDGDAQPRETWG
  KKIDFLLSVVGFAVDLANVWRFPYLCYKNGGGAFLIPYTLFLIIAGMPLFYMELALGQYN
  REGAATVWKICPFFKGVGYAVILIALYVGFYYNVIIAWSLYYLFSSFTLNLPWTDCGHTW
  NSPNCTDPKLLNGSVLGNHTKYSKYKFTPAAEFYERGVLHLHESSGIHDIGLPQWQLLLC
  LMVVVIVLYFSLWKGVKTSGKVVWITATLPYFVLFVLLVHGVTLPGASNGINAYLHIDFY
  RLKEATVWIDAATQIFFSLGAGFGVLIAFASYNKFDNNCYRDALLTSSINCITSFVSGFA
  IFSILGYMAHEHKVNIEDVATEGAGLVFILYPEAISTLSGSTFWAVVFFVMLLALGLDSS
  MGGMEAVITGLADDFQVLKRHRKLFTFGVTFSTFLLALFCITKGGIYVLTLLDTFAAGTS
  ILFAVLMEAIGVSWFYGVDRFSNDIQQMMGFRPGLYWRLCWKFVSPAFLLFVVVVSIINF
  KPLTYDDYIFPPWANWVGWGIALSSMVLVPIYVIYKFLSTQGSLWERLAYGITPENEHHL
  VAQRDIRQFQLQHWLAI
• Function: Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline). Can also mediate sodium- and chloride-dependent transport of dopamine.
• KEGG Pathway: Sy.ptic vesicle cycle (hsa04721)
• Reactome Pathway:
  Defective SLC6A2 causes orthostatic intolerance (OI) (R-HSA-5619109)
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Postural orthostatic tachycardia syndrome	DIS1O1QK	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Sodium-dependent noradrenaline transporter (SLC6A2) decreases the response to substance of Arsenic trioxide.	[11]
Nortriptyline	DM4KDYJ	Approved	Sodium-dependent noradrenaline transporter (SLC6A2) affects the response to substance of Nortriptyline.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Norepinephrine	DMOUC09	Approved	Sodium-dependent noradrenaline transporter (SLC6A2) decreases the uptake of Norepinephrine.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[2]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[3]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[4]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[5]
Cocaine	DMSOX7I	Approved	Cocaine decreases the activity of Sodium-dependent noradrenaline transporter (SLC6A2).	[6]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[7]
Amphetamine	DMSZQAK	Approved	Amphetamine decreases the activity of Sodium-dependent noradrenaline transporter (SLC6A2).	[6]
Dextroamphetamine	DMMIHVP	Approved	Dextroamphetamine decreases the activity of Sodium-dependent noradrenaline transporter (SLC6A2).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[4]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Sodium-dependent noradrenaline transporter (SLC6A2).	[9]
Methylenedioxymethamphetamine	DMYVU47	Investigative	Methylenedioxymethamphetamine decreases the activity of Sodium-dependent noradrenaline transporter (SLC6A2).	[8]

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-dependent noradrenaline transporter (SLC6A2).	[10]

References

• [1] Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 2000 Feb 24;342(8):541-9. doi: 10.1056/NEJM200002243420803.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [6] Regulation of the human norepinephrine transporter by cocaine and amphetamine. J Pharmacol Exp Ther. 2000 Dec;295(3):951-9.
• [7] 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.
• [8] Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR. Neurotoxicology. 2019 May;72:95-100. doi: 10.1016/j.neuro.2019.02.011. Epub 2019 Feb 15.
• [9] 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.
• [10] 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.
• [11] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [12] Familial orthostatic tachycardia due to norepinephrine transporter deficiency. Ann N Y Acad Sci. 2001 Jun;940:527-43. doi: 10.1111/j.1749-6632.2001.tb03703.x.
• [13] Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression. JAMA. 2006 Oct 4;296(13):1609-18. doi: 10.1001/jama.296.13.1609.