Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8BY933)

• DOT Name: Organic anion transporter 3 (SLC22A8)
• Synonyms: hOAT3; Organic anion/dicarboxylate exchanger; Solute carrier family 22 member 8
• Gene Name: SLC22A8
• UniProt ID: S22A8_HUMAN
• Pfam ID: PF00083
• Sequence:
  MTFSEILDRVGSMGHFQFLHVAILGLPILNMANHNLLQIFTAATPVHHCRPPHNASTGPW
  VLPMGPNGKPERCLRFVHPPNASLPNDTQRAMEPCLDGWVYNSTKDSIVTEWDLVCNSNK
  LKEMAQSIFMAGILIGGLVLGDLSDRFGRRPILTCSYLLLAASGSGAAFSPTFPIYMVFR
  FLCGFGISGITLSTVILNVEWVPTRMRAIMSTALGYCYTFGQFILPGLAYAIPQWRWLQL
  TVSIPFFVFFLSSWWTPESIRWLVLSGKSSKALKILRRVAVFNGKKEEGERLSLEELKLN
  LQKEISLAKAKYTASDLFRIPMLRRMTFCLSLAWFATGFAYYSLAMGVEEFGVNLYILQI
  IFGGVDVPAKFITILSLSYLGRHTTQAAALLLAGGAILALTFVPLDLQTVRTVLAVFGKG
  CLSSSFSCLFLYTSELYPTVIRQTGMGVSNLWTRVGSMVSPLVKITGEVQPFIPNIIYGI
  TALLGGSAALFLPETLNQPLPETIEDLENWSLRAKKPKQEPEVEKASQRIPLQPHGPGLG
  SS
• Function: Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient. Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain. E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange. Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule. Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate. 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. May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside. May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate. Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor). May contribute to the release of cortisol in the adrenals. Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile. Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body.
• Tissue Specificity: Strongly expressed in kidney . Weaker expression in brain and skeletal muscle . Expressed in adrenal glands .
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway:
  Ciprofloxacin ADME (R-HSA-9793528)
  Organic anion transport (R-HSA-561048)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Organic anion transporter 3 (SLC22A8) increases the response to substance of Methotrexate.	[13]
Cidofovir	DMA13GD	Approved	Organic anion transporter 3 (SLC22A8) increases the response to substance of Cidofovir.	[14]
PMEA	DMBKVJY	Investigative	Organic anion transporter 3 (SLC22A8) increases the response to substance of PMEA.	[14]

This DOT Affected the Regulation of Drug Effects of 23 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dinoprostone	DMTYOPD	Approved	Organic anion transporter 3 (SLC22A8) affects the transport of Dinoprostone.	[15]
Tetracycline	DMZA017	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Tetracycline.	[16]
Cimetidine	DMH61ZB	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Cimetidine.	[17]
Famotidine	DMRL3AB	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Famotidine.	[18]
Ranitidine	DM0GUSX	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Ranitidine.	[17]
Dehydroepiandrosterone sulfate	DM4Q80H	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Dehydroepiandrosterone sulfate.	[19]
Enalaprilat	DMFYAM1	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Enalaprilat.	[20]
Cefaclor	DMJXDGC	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Cefaclor.	[19]
Cefdinir	DMJ7A0H	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Cefdinir.	[19]
Ceftibuten	DMWV2AG	Approved	Organic anion transporter 3 (SLC22A8) increases the uptake of Ceftibuten.	[19]
Benzylpenicillin	DMS9503	Phase 3	Organic anion transporter 3 (SLC22A8) increases the uptake of Benzylpenicillin.	[21]
Taurocholic acid	DM2LZ8F	Phase 1/2	Organic anion transporter 3 (SLC22A8) affects the transport of Taurocholic acid.	[15]
Cephaloridine	DM4Y95F	Withdrawn from market	Organic anion transporter 3 (SLC22A8) increases the uptake of Cephaloridine.	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	Organic anion transporter 3 (SLC22A8) increases the uptake of 3R14S-OCHRATOXIN A.	[19]
Aminohippuric acid	DMUN54G	Investigative	Organic anion transporter 3 (SLC22A8) increases the uptake of Aminohippuric acid.	[19]
Daidzein	DMRFTJX	Investigative	Organic anion transporter 3 (SLC22A8) increases the uptake of Daidzein.	[22]
[3H]cAMP	DMZRQU7	Investigative	Organic anion transporter 3 (SLC22A8) affects the transport of [3H]cAMP.	[15]
Uric acid	DMA1MKT	Investigative	Organic anion transporter 3 (SLC22A8) affects the transport of Uric acid.	[15]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Organic anion transporter 3 (SLC22A8) increases the import of [3H]estrone-3-sulphate.	[12]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Investigative	Organic anion transporter 3 (SLC22A8) affects the transport of [3H]estradiol-17beta-glucuronide.	[15]
[3H]folinic acid	DME0XHN	Investigative	Organic anion transporter 3 (SLC22A8) increases the uptake of [3H]folinic acid.	[19]
6-Carboxyfluorescein	DMWTMDH	Investigative	Organic anion transporter 3 (SLC22A8) increases the import of 6-Carboxyfluorescein.	[12]
Cephalosporin C	DMYW3ZG	Investigative	Organic anion transporter 3 (SLC22A8) affects the secretion of Cephalosporin C.	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Organic anion transporter 3 (SLC22A8).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Organic anion transporter 3 (SLC22A8).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of Organic anion transporter 3 (SLC22A8).	[2]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Organic anion transporter 3 (SLC22A8).	[3]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Organic anion transporter 3 (SLC22A8).	[4]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Organic anion transporter 3 (SLC22A8).	[5]
Valsartan	DMREUQ6	Approved	Valsartan increases the expression of Organic anion transporter 3 (SLC22A8).	[6]
Probenecid	DMMFWOJ	Approved	Probenecid decreases the expression of Organic anion transporter 3 (SLC22A8).	[7]
Succinic acid	DMDWICP	Approved	Succinic acid increases the activity of Organic anion transporter 3 (SLC22A8).	[8]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 decreases the activity of Organic anion transporter 3 (SLC22A8).	[2]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the activity of Organic anion transporter 3 (SLC22A8).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the activity of Organic anion transporter 3 (SLC22A8).	[11]
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 Organic anion transporter 3 (SLC22A8).	[12]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid decreases the activity of Organic anion transporter 3 (SLC22A8).	[10]
Wogonin	DMGCF51	Investigative	Wogonin decreases the activity of Organic anion transporter 3 (SLC22A8).	[2]
WEDELOLACTONE	DMHL3YV	Investigative	WEDELOLACTONE decreases the activity of Organic anion transporter 3 (SLC22A8).	[2]
Glutarate	DMPUFDS	Investigative	Glutarate increases the activity of Organic anion transporter 3 (SLC22A8).	[12]

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] 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] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [4] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [5] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [6] Uric acid accumulation in the kidney triggers mast cell degranulation and aggravates renal oxidative stress. Toxicology. 2023 Jan 1;483:153387. doi: 10.1016/j.tox.2022.153387. Epub 2022 Dec 1.
• [7] Targeting organic anion transporter 3 with probenecid as a novel anti-influenza a virus strategy. Antimicrob Agents Chemother. 2013 Jan;57(1):475-83. doi: 10.1128/AAC.01532-12. Epub 2012 Nov 5.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.
• [13] 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.
• [14] Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir. Toxicol In Vitro. 2015 Feb;29(1):251-8. doi: 10.1016/j.tiv.2014.10.019.
• [15] Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86.
• [16] Human organic anion transporters mediate the transport of tetracycline. Jpn J Pharmacol. 2002 Jan;88(1):69-76.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule. Pharmaceutics. 2020 Sep 30;12(10):935. doi: 10.3390/pharmaceutics12100935.
• [21] Characterization of the uptake of organic anion transporter (OAT) 1 and OAT3 substrates by human kidney slices. J Pharmacol Exp Ther. 2007 Apr;321(1):362-9. doi: 10.1124/jpet.106.113076. Epub 2007 Jan 25.
• [22] 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.