Details of Drug Off-Target (DOT)

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

• DOT Name: Solute carrier family 22 member 3 (SLC22A3)
• Synonyms: Extraneuronal monoamine transporter; EMT; Organic cation transporter 3; OCT3
• Gene Name: SLC22A3
• UniProt ID: S22A3_HUMAN
• PDB ID: 7ZH0; 7ZH6; 7ZHA
• Pfam ID: PF07690
• Sequence:
  MPSFDEALQRVGEFGRFQRRVFLLLCLTGVTFAFLFVGVVFLGTQPDHYWCRGPSAAALA
  ERCGWSPEEEWNRTAPASRGPEPPERRGRCQRYLLEAANDSASATSALSCADPLAAFPNR
  SAPLVPCRGGWRYAQAHSTIVSEFDLVCVNAWMLDLTQAILNLGFLTGAFTLGYAADRYG
  RIVIYLLSCLGVGVTGVVVAFAPNFPVFVIFRFLQGVFGKGTWMTCYVIVTEIVGSKQRR
  IVGIVIQMFFTLGIIILPGIAYFIPNWQGIQLAITLPSFLFLLYYWVVPESPRWLITRKK
  GDKALQILRRIAKCNGKYLSSNYSEITVTDEEVSNPSFLDLVRTPQMRKCTLILMFAWFT
  SAVVYQGLVMRLGIIGGNLYIDFFISGVVELPGALLILLTIERLGRRLPFAASNIVAGVA
  CLVTAFLPEGIAWLRTTVATLGRLGITMAFEIVYLVNSELYPTTLRNFGVSLCSGLCDFG
  GIIAPFLLFRLAAVWLELPLIIFGILASICGGLVMLLPETKGIALPETVDDVEKLGSPHS
  CKCGRNKKTPVSRSHL
• Function: Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics. Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient. Functions as a Na(+)- and Cl(-)-independent, bidirectional uniporter. Implicated in monoamine neurotransmitters uptake such as dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine, serotonin and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the brain. Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with low efficiency. May be involved in the uptake and disposition of cationic compounds by renal clearance from the blood flow. May contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable). Mediates the transport of polyamine spermidine and putrescine. Mediates the bidirectional transport of polyamine agmatine. Also transports guanidine. May also mediate intracellular transport of organic cations, thereby playing a role in amine metabolism and intracellular signaling.
• Tissue Specificity: Expressed in liver . Expressed in intestine . Expressed in kidney in proximal tubular cells . Expressed in placenta . Expressed throughout the brain, including cerebral cortex, cerebrellum, substancia nigra, medulla oblongata, hippocampus, caudate nucleus, nucleus accumbens and pons with low levels of expression detected in nearly all brain regions . In testis, mostly localized to peritubular myoid cells and Leydig cells, and weakly expressed in developing germ cells . Expressed in tracheal and bronchial epithelium of the respiratory tract, where it localizes to the apical membrane of ciliated cells, the entire membrane of basal cells and the basolateral membrane of intermediate cells . Expressed in skeletal muscle, adrenal gland, heart, prostate, aorta, salivary gland, adrenal gland, uterus, lymph node, lung, trachea and spinal cord . Expressed in fetal lung and liver .
• KEGG Pathway: Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Organic cation transport (R-HSA-549127)
  Abacavir transmembrane transport (R-HSA-2161517)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Solute carrier family 22 member 3 (SLC22A3) affects the response to substance of Paclitaxel.	[22]
Vinblastine	DM5TVS3	Approved	Solute carrier family 22 member 3 (SLC22A3) affects the response to substance of Vinblastine.	[22]

This DOT Affected the Regulation of Drug Effects of 16 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dopamine	DMPGUCF	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Dopamine.	[23]
Cimetidine	DMH61ZB	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the transport of Cimetidine.	[24]
Ergotidine	DM78IME	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Ergotidine.	[23]
Epinephrine	DM3KJBC	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Epinephrine.	[23]
Norepinephrine	DMOUC09	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Norepinephrine.	[23]
Lamivudine	DMI347A	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Lamivudine.	[25]
Atropine	DMEN6X7	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Atropine.	[26]
Salmeterol	DMIEU69	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Salmeterol.	[27]
Sulpiride	DMF54ZG	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Sulpiride.	[28]
Arformoterol	DMYM974	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Arformoterol.	[27]
Trimethoprim	DMM7CHK	Approved	Solute carrier family 22 member 3 (SLC22A3) increases the transport of Trimethoprim.	[24]
Etilefrine	DM67PWD	Withdrawn from market	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Etilefrine.	[26]
Serotonin	DMOFCRY	Investigative	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Serotonin.	[23]
Ethidium	DMMEQUR	Investigative	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Ethidium.	[29]
[14C]TEA	DM6SFYH	Investigative	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of [14C]TEA.	[30]
Guanidine	DM4GO8H	Investigative	Solute carrier family 22 member 3 (SLC22A3) increases the uptake of Guanidine.	[30]

26 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 3 (SLC22A3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Solute carrier family 22 member 3 (SLC22A3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Solute carrier family 22 member 3 (SLC22A3).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Solute carrier family 22 member 3 (SLC22A3).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Solute carrier family 22 member 3 (SLC22A3).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the activity of Solute carrier family 22 member 3 (SLC22A3).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Solute carrier family 22 member 3 (SLC22A3).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[13]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[14]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[15]
Famotidine	DMRL3AB	Approved	Famotidine decreases the activity of Solute carrier family 22 member 3 (SLC22A3).	[16]
Phenoxybenzamine	DM8KSQH	Approved	Phenoxybenzamine decreases the activity of Solute carrier family 22 member 3 (SLC22A3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier family 22 member 3 (SLC22A3).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Solute carrier family 22 member 3 (SLC22A3).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[20]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Solute carrier family 22 member 3 (SLC22A3).	[7]
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 3 (SLC22A3).	[21]
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Investigative	(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE decreases the activity of Solute carrier family 22 member 3 (SLC22A3).	[12]
NORHARMANE	DMKYQWG	Investigative	NORHARMANE decreases the activity of Solute carrier family 22 member 3 (SLC22A3).	[21]

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 3 (SLC22A3).	[17]

References

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• [12] Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol. 2002 Jul;136(6):829-36.
• [13] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
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• [16] Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005 Dec;315(3):1288-97.
• [17] 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.
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• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [21] 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.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
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