Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGFK1AL)

• DOT Name: Solute carrier family 22 member 2 (SLC22A2)
• Synonyms: Organic cation transporter 2; hOCT2
• Gene Name: SLC22A2
• UniProt ID: S22A2_HUMAN
• PDB ID: 8ET9
• Pfam ID: PF00083
• Sequence:
  MPTTVDDVLEHGGEFHFFQKQMFFLLALLSATFAPIYVGIVFLGFTPDHRCRSPGVAELS
  LRCGWSPAEELNYTVPGPGPAGEASPRQCRRYEVDWNQSTFDCVDPLASLDTNRSRLPLG
  PCRDGWVYETPGSSIVTEFNLVCANSWMLDLFQSSVNVGFFIGSMSIGYIADRFGRKLCL
  LTTVLINAAAGVLMAISPTYTWMLIFRLIQGLVSKAGWLIGYILITEFVGRRYRRTVGIF
  YQVAYTVGLLVLAGVAYALPHWRWLQFTVSLPNFFFLLYYWCIPESPRWLISQNKNAEAM
  RIIKHIAKKNGKSLPASLQRLRLEEETGKKLNPSFLDLVRTPQIRKHTMILMYNWFTSSV
  LYQGLIMHMGLAGDNIYLDFFYSALVEFPAAFMIILTIDRIGRRYPWAASNMVAGAACLA
  SVFIPGDLQWLKIIISCLGRMGITMAYEIVCLVNAELYPTFIRNLGVHICSSMCDIGGII
  TPFLVYRLTNIWLELPLMVFGVLGLVAGGLVLLLPETKGKALPETIEEAENMQRPRKNKE
  KMIYLQVQKLDIPLN
• Function: Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics. Functions as a Na(+)-independent, bidirectional uniporter. Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient. However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached. Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow. Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters. Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system. Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium. Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN). Mediates the uptake and efflux of quaternary ammonium compound choline. Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine. Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable); [Isoform 2]: In contrast with isoform 1, not able to transport guanidine, creatinine, cimetidine and metformin.
• Tissue Specificity: Mainly expressed in kidney, in the cortex and medulla . Localized in testis, mostly to peritubular myoid cells and Leydig cells and also detected along the basal membrane of Sertoli cells . Expressed in brain, in neurons of the cerebral cortex and in various subcortical nuclei . In the brain, also detected in the dopaminergic regions of the substantia nigra . Expressed in tracheal and bronchial ciliated epithelium in the respiratory tract . Also detected in secretory phase endometrium, in scattered stromal cells . Expressed in spleen, placenta, small intestine and spinal cord . Weakly expressed in prostate, uterus and lung .; [Isoform 2]: Mainly expressed in kidney, bone marrow and testis . Expressed in colon, skeletal muscle, spinal cord, placenta and liver .
• KEGG Pathway: Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Abacavir transmembrane transport (R-HSA-2161517)
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Organic cation transport (R-HSA-549127)
  Neurotransmitter clearance (R-HSA-112311)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Solute carrier family 22 member 2 (SLC22A2) decreases the response to substance of Cisplatin.	[8]
Aspirin	DM672AH	Approved	Solute carrier family 22 member 2 (SLC22A2) affects the response to substance of Aspirin.	[9]
Nicotine	DMWX5CO	Approved	Solute carrier family 22 member 2 (SLC22A2) affects the response to substance of Nicotine.	[10]
Cimetidine	DMH61ZB	Approved	Solute carrier family 22 member 2 (SLC22A2) decreases the response to substance of Cimetidine.	[8]
Paraquat	DMR8O3X	Investigative	Solute carrier family 22 member 2 (SLC22A2) increases the response to substance of Paraquat.	[15]

This DOT Affected the Regulation of Drug Effects of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gentamicin	DMKINJO	Approved	Solute carrier family 22 member 2 (SLC22A2) increases the transport of Gentamicin.	[11]
Lamivudine	DMI347A	Approved	Solute carrier family 22 member 2 (SLC22A2) increases the uptake of Lamivudine.	[12]
Famotidine	DMRL3AB	Approved	Solute carrier family 22 member 2 (SLC22A2) increases the uptake of Famotidine.	[13]
Ranitidine	DM0GUSX	Approved	Solute carrier family 22 member 2 (SLC22A2) increases the uptake of Ranitidine.	[13]
N1-methylnicotinamide	DM16PWF	Phase 2/3	Solute carrier family 22 member 2 (SLC22A2) increases the import of N1-methylnicotinamide.	[14]
Ethidium	DMMEQUR	Investigative	Solute carrier family 22 member 2 (SLC22A2) increases the uptake of Ethidium.	[16]
[14C]TEA	DM6SFYH	Investigative	Solute carrier family 22 member 2 (SLC22A2) decreases the uptake of [14C]TEA.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Solute carrier family 22 member 2 (SLC22A2).	[1]
Piroxicam	DMTK234	Approved	Piroxicam decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[2]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[2]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[2]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[2]
Quinine	DMSWYF5	Approved	Quinine decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[3]
Phenoxybenzamine	DM8KSQH	Approved	Phenoxybenzamine decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[4]
Trospium chloride	DM32XZT	Approved	Trospium chloride decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[5]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[7]
NORHARMANE	DMKYQWG	Investigative	NORHARMANE decreases the activity of Solute carrier family 22 member 2 (SLC22A2).	[7]

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 Solute carrier family 22 member 2 (SLC22A2).	[6]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther. 2002 Nov;303(2):534-9.
• [3] Involvement of aryl hydrocarbon receptor in the cytotoxicity of corannulene and its derivatives. Toxicol Lett. 2020 Mar 15;321:114-121. doi: 10.1016/j.toxlet.2019.12.012. Epub 2019 Dec 9.
• [4] Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol. 2002 Jul;136(6):829-36.
• [5] Expression of drug transporters and drug metabolizing enzymes in the bladder urothelium in man and affinity of the bladder spasmolytic trospium chloride to transporters likely involved in its pharmacokinetics. Mol Pharm. 2015 Jan 5;12(1):171-8.
• [6] 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.
• [7] Inhibition of organic cation transporter (OCT) activities by carcinogenic heterocyclic aromatic amines. Toxicol In Vitro. 2019 Feb;54:10-22. doi: 10.1016/j.tiv.2018.08.015. Epub 2018 Sep 3.
• [8] Ameliorative effects of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity in Chinese cancer patients. Food Chem Toxicol. 2012 Jul;50(7):2289-93. doi: 10.1016/j.fct.2012.03.077. Epub 2012 Apr 16.
• [9] Possible association of SLC22A2 polymorphisms with aspirin-intolerant asthma. Int Arch Allergy Immunol. 2011;155(4):395-402. doi: 10.1159/000321267. Epub 2011 Feb 22.
• [10] Organic cation transporter variation and response to smoking cessation therapies. Nicotine Tob Res. 2014 Dec;16(12):1638-46. doi: 10.1093/ntr/ntu161. Epub 2014 Aug 20.
• [11] Organic Cation Transporter 2 Overexpression May Confer an Increased Risk of Gentamicin-Induced Nephrotoxicity. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5573-80. doi: 10.1128/AAC.00907-16. Print 2016 Sep.
• [12] Transport of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J Pharmacol Exp Ther. 2009 Apr;329(1):252-61. doi: 10.1124/jpet.108.146225. Epub 2009 Jan 13.
• [13] A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther. 2005 Oct;315(1):337-45.
• [14] Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997 Jul;16(7):871-81.
• [15] Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family. J Pharmacol Exp Ther. 2007 Aug;322(2):695-700. doi: 10.1124/jpet.107.123554. Epub 2007 May 10.
• [16] Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule. Am J Physiol Renal Physiol. 2009 Jun;296(6):F1504-13. doi: 10.1152/ajprenal.90754.2008. Epub 2009 Apr 8.
• [17] Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population. Drug Metab Dispos. 2007 Apr;35(4):667-75. doi: 10.1124/dmd.106.013581. Epub 2007 Jan 12.