Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7817I4)

• DOT Name: Solute carrier family 22 member 1 (SLC22A1)
• Synonyms: Organic cation transporter 1; hOCT1
• Gene Name: SLC22A1
• UniProt ID: S22A1_HUMAN
• PDB ID: 8ET6; 8ET7; 8ET8; 8SC1; 8SC2; 8SC3; 8SC4; 8SC6
• Pfam ID: PF00083
• Sequence:
  MPTVDDILEQVGESGWFQKQAFLILCLLSAAFAPICVGIVFLGFTPDHHCQSPGVAELSQ
  RCGWSPAEELNYTVPGLGPAGEAFLGQCRRYEVDWNQSALSCVDPLASLATNRSHLPLGP
  CQDGWVYDTPGSSIVTEFNLVCADSWKLDLFQSCLNAGFLFGSLGVGYFADRFGRKLCLL
  GTVLVNAVSGVLMAFSPNYMSMLLFRLLQGLVSKGNWMAGYTLITEFVGSGSRRTVAIMY
  QMAFTVGLVALTGLAYALPHWRWLQLAVSLPTFLFLLYYWCVPESPRWLLSQKRNTEAIK
  IMDHIAQKNGKLPPADLKMLSLEEDVTEKLSPSFADLFRTPRLRKRTFILMYLWFTDSVL
  YQGLILHMGATSGNLYLDFLYSALVEIPGAFIALITIDRVGRIYPMAMSNLLAGAACLVM
  IFISPDLHWLNIIIMCVGRMGITIAIQMICLVNAELYPTFVRNLGVMVCSSLCDIGGIIT
  PFIVFRLREVWQALPLILFAVLGLLAAGVTLLLPETKGVALPETMKDAENLGRKAKPKEN
  TIYLKVQTSEPSGT
• 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 pH- and Na(+)-independent, bidirectional transporter. Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity. Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors. Primarily 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. Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation. Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline. Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover. Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism. 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. Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency. Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) ; [Isoform 1]: Mediates the uptake of 1-methyl-4-phenylpyridinium (MPP(+)); [Isoform 2]: Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)); [Isoform 3]: Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)); [Isoform 4]: Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).
• Tissue Specificity: Widely expressed with high level in liver . In liver, expressed around the central vein . Expressed in kidney . Expressed in small intestine enterocytes . Localized to peritubular myoid cells, Leydig cells and moderately to the basal membrane of Sertoli cells in testes . Expressed in tracheal and bronchial ciliated epithelium in the respiratory tract . Also expressed in skeletal muscle, stomach, spleen, heart, placentacolon, brain, granulycytes and lympohocytes .; [Isoform 1]: Expressed in liver and in glial cell lines.; [Isoform 2]: Expressed in liver and in glial cell lines.; [Isoform 3]: Expressed in glial cell lines. Not expressed in liver.; [Isoform 4]: Expressed in glial cell lines. Not expressed in liver.
• KEGG Pathway:
  Bile secretion (hsa04976)
  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)
  Ciprofloxacin ADME (R-HSA-9793528)
  Neurotransmitter clearance (R-HSA-112311)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Solute carrier family 22 member 1 (SLC22A1) increases the uptake of Quercetin.	[17]
Lamivudine	DMI347A	Approved	Solute carrier family 22 member 1 (SLC22A1) increases the uptake of Lamivudine.	[18]
Famotidine	DMRL3AB	Approved	Solute carrier family 22 member 1 (SLC22A1) affects the transport of Famotidine.	[19]
Ranitidine	DM0GUSX	Approved	Solute carrier family 22 member 1 (SLC22A1) affects the transport of Ranitidine.	[19]
Trospium chloride	DM32XZT	Approved	Solute carrier family 22 member 1 (SLC22A1) increases the metabolism of Trospium chloride.	[20]
Ethidium	DMMEQUR	Investigative	Solute carrier family 22 member 1 (SLC22A1) increases the uptake of Ethidium.	[21]

27 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 22 member 1 (SLC22A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier family 22 member 1 (SLC22A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[2]
Progesterone	DMUY35B	Approved	Progesterone decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Solute carrier family 22 member 1 (SLC22A1).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[9]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[10]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[9]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[9]
Lindane	DMB8CNL	Approved	Lindane decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[11]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[12]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[9]
Ketoprofen	DMRKXPT	Approved	Ketoprofen decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[9]
Quinine	DMSWYF5	Approved	Quinine decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[13]
Phenoxybenzamine	DM8KSQH	Approved	Phenoxybenzamine decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Solute carrier family 22 member 1 (SLC22A1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[15]
Hyperforin	DM2L3PE	Investigative	Hyperforin decreases the expression of Solute carrier family 22 member 1 (SLC22A1).	[10]
chlordane	DMMHU8G	Investigative	chlordane decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[11]
NORHARMANE	DMKYQWG	Investigative	NORHARMANE decreases the activity of Solute carrier family 22 member 1 (SLC22A1).	[16]

References

• [1] 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.
• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol. 2002 Jul;136(6):829-36.
• [6] Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4 upregulation in primary human hepatocytes. Pharmacol Rep. 2013;65(5):1322-35. doi: 10.1016/s1734-1140(13)71491-9.
• [7] 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.
• [8] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [9] 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.
• [10] The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for ("squelching") SRC-1 coactivator. Br J Pharmacol. 2016 May;173(10):1703-15. doi: 10.1111/bph.13472. Epub 2016 Apr 8.
• [11] Regulation of hepatic drug transporter activity and expression by organochlorine pesticides. J Biochem Mol Toxicol. 2014 Mar;28(3):119-28.
• [12] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Inhibition of SLC drug transporter activities by environmental bisphenols. Toxicol In Vitro. 2017 Apr;40:34-44. doi: 10.1016/j.tiv.2016.12.009. Epub 2016 Dec 15.
• [16] 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.
• [17] Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin. Naunyn Schmiedebergs Arch Pharmacol. 2014 Sep;387(9):883-91. doi: 10.1007/s00210-014-1000-6. Epub 2014 Jun 20.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.