Details of Drug Off-Target (DOT)

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

• DOT Name: Solute carrier family 22 member 6 (SLC22A6)
• Synonyms: Organic anion transporter 1; hOAT1; PAH transporter; hPAHT; Renal organic anion transporter 1; hROAT1
• Gene Name: SLC22A6
• UniProt ID: S22A6_HUMAN
• Pfam ID: PF00083
• Sequence:
  MAFNDLLQQVGGVGRFQQIQVTLVVLPLLLMASHNTLQNFTAAIPTHHCRPPADANLSKN
  GGLEVWLPRDRQGQPESCLRFTSPQWGLPFLNGTEANGTGATEPCTDGWIYDNSTFPSTI
  VTEWDLVCSHRALRQLAQSLYMVGVLLGAMVFGYLADRLGRRKVLILNYLQTAVSGTCAA
  FAPNFPIYCAFRLLSGMALAGISLNCMTLNVEWMPIHTRACVGTLIGYVYSLGQFLLAGV
  AYAVPHWRHLQLLVSAPFFAFFIYSWFFIESARWHSSSGRLDLTLRALQRVARINGKREE
  GAKLSMEVLRASLQKELTMGKGQASAMELLRCPTLRHLFLCLSMLWFATSFAYYGLVMDL
  QGFGVSIYLIQVIFGAVDLPAKLVGFLVINSLGRRPAQMAALLLAGICILLNGVIPQDQS
  IVRTSLAVLGKGCLAASFNCIFLYTGELYPTMIRQTGMGMGSTMARVGSIVSPLVSMTAE
  LYPSMPLFIYGAVPVAASAVTVLLPETLGQPLPDTVQDLESRWAPTQKEAGIYPRKGKQT
  RQQQEHQKYMVPLQASAQEKNGL
• Function: Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate. Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine. Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins. Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion. Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP. Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain. May transport glutamate. Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body. Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate. Xenobiotics include the mycotoxin ochratoxin (OTA). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier.
• Tissue Specificity: Strongly expressed in kidney . Expressed at lower level in liver, skeletal muscle, brain and placenta . In kidney, found at the basolateral membrane of the proximal tubule . In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and vascular endothelial cells .
• Reactome Pathway: Organic anion transport (R-HSA-561048)

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
Methotrexate	DM2TEOL	Approved	Solute carrier family 22 member 6 (SLC22A6) increases the response to substance of Methotrexate.	[9]
PMEA	DMBKVJY	Investigative	Solute carrier family 22 member 6 (SLC22A6) increases the response to substance of PMEA.	[16]

This DOT Affected the Regulation of Drug Effects of 12 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tetracycline	DMZA017	Approved	Solute carrier family 22 member 6 (SLC22A6) increases the export of Tetracycline.	[10]
Cimetidine	DMH61ZB	Approved	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Cimetidine.	[11]
Ranitidine	DM0GUSX	Approved	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Ranitidine.	[12]
Cefdinir	DMJ7A0H	Approved	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Cefdinir.	[13]
Ceftibuten	DMWV2AG	Approved	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Ceftibuten.	[13]
Genistein	DM0JETC	Phase 2/3	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Genistein.	[14]
Cephaloridine	DM4Y95F	Withdrawn from market	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Cephaloridine.	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of 3R14S-OCHRATOXIN A.	[13]
Uric acid	DMA1MKT	Investigative	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Uric acid.	[15]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of [3H]estrone-3-sulphate.	[13]
[3H]folinic acid	DME0XHN	Investigative	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of [3H]folinic acid.	[13]
Glutarate	DMPUFDS	Investigative	Solute carrier family 22 member 6 (SLC22A6) increases the uptake of Glutarate.	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 6 (SLC22A6).	[1]
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[2]
Aspirin	DM672AH	Approved	Aspirin decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Piroxicam	DMTK234	Approved	Piroxicam decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Ketoprofen	DMRKXPT	Approved	Ketoprofen decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Salicyclic acid	DM2F8XZ	Approved	Salicyclic acid decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
Probenecid	DMMFWOJ	Approved	Probenecid decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[4]
Succinic acid	DMDWICP	Approved	Succinic acid increases the activity of Solute carrier family 22 member 6 (SLC22A6).	[5]
Chloride	DM1TJXA	Phase 3	Chloride increases the activity of Solute carrier family 22 member 6 (SLC22A6).	[6]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[2]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[2]
Phenacetin	DMRQAM0	Withdrawn from market	Phenacetin decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[3]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[8]
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 6 (SLC22A6).	[4]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[8]
Wogonin	DMGCF51	Investigative	Wogonin decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[2]
WEDELOLACTONE	DMHL3YV	Investigative	WEDELOLACTONE decreases the activity of Solute carrier family 22 member 6 (SLC22A6).	[2]

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 6 (SLC22A6).	[7]

References

• [1] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [2] Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy. Toxicol Sci. 2020 Jun 1;175(2):279-291. doi: 10.1093/toxsci/kfaa033.
• [3] 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.
• [4] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.
• [5] Lack of efflux of diglycolic acid from proximal tubule cells leads to its accumulation and to toxicity of diethylene glycol. Toxicol Lett. 2023 Apr 15;379:48-55. doi: 10.1016/j.toxlet.2023.03.007. Epub 2023 Mar 22.
• [6] The chloride dependence of the human organic anion transporter 1 (hOAT1) is blunted by mutation of a single amino acid. J Biol Chem. 2007 May 4;282(18):13402-9. doi: 10.1074/jbc.M609849200. Epub 2007 Mar 12.
• [7] 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.
• [8] From the Cover: Identification of Natural Products as Inhibitors of Human Organic Anion Transporters (OAT1 and OAT3) and Their Protective Effect on Mercury-Induced Toxicity. Toxicol Sci. 2018 Feb 1;161(2):321-334. doi: 10.1093/toxsci/kfx216.
• [9] P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate. Toxicol Appl Pharmacol. 2016 Sep 1;306:27-35. doi: 10.1016/j.taap.2016.06.030. Epub 2016 Jul 1.
• [10] Human organic anion transporters mediate the transport of tetracycline. Jpn J Pharmacol. 2002 Jan;88(1):69-76.
• [11] Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A). Eur J Pharmacol. 2004 Oct 25;503(1-3):25-30.
• [12] 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.
• [13] Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol. 2005 Oct 1;70(7):1104-13.
• [14] Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6). Biochem Pharmacol. 2011 Apr 1;81(7):942-9.
• [15] Urate transport via human PAH transporter hOAT1 and its gene structure. Kidney Int. 2003 Jan;63(1):143-55.
• [16] Interactions with selected drug renal transporters and transporter-mediated cytotoxicity in antiviral agents from the group of acyclic nucleoside phosphonates. Toxicology. 2013 Sep 15;311(3):135-46. doi: 10.1016/j.tox.2013.07.004. Epub 2013 Jul 13.