Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKTNH1W)

• DOT Name: Solute carrier family 22 member 7 (SLC22A7)
• Synonyms: Novel liver transporter; NLT; Organic anion transporter 2; hOAT2
• Gene Name: SLC22A7
• UniProt ID: S22A7_HUMAN
• Pfam ID: PF07690
• Sequence:
  MGFEELLEQVGGFGPFQLRNVALLALPRVLLPLHFLLPIFLAAVPAHRCALPGAPANFSH
  QDVWLEAHLPREPDGTLSSCLRFAYPQALPNTTLGEERQSRGELEDEPATVPCSQGWEYD
  HSEFSSTIATESQWDLVCEQKGLNRAASTFFFAGVLVGAVAFGYLSDRFGRRRLLLVAYV
  STLVLGLASAASVSYVMFAITRTLTGSALAGFTIIVMPLELEWLDVEHRTVAGVLSSTFW
  TGGVMLLALVGYLIRDWRWLLLAVTLPCAPGILSLWWVPESARWLLTQGHVKEAHRYLLH
  CARLNGRPVCEDSFSQEAVSKVAAGERVVRRPSYLDLFRTPRLRHISLCCVVVWFGVNFS
  YYGLSLDVSGLGLNVYQTQLLFGAVELPSKLLVYLSVRYAGRRLTQAGTLLGTALAFGTR
  LLVSSDMKSWSTVLAVMGKAFSEAAFTTAYLFTSELYPTVLRQTGMGLTALVGRLGGSLA
  PLAALLDGVWLSLPKLTYGGIALLAAGTALLLPETRQAQLPETIQDVERKSAPTSLQEEE
  MPMKQVQN
• Function: [Isoform 2]: Functions as a Na(+)-independent bidirectional multispecific transporter. Contributes to the renal and hepatic elimination of endogenous organic compounds from the systemic circulation into the urine and bile, respectively. Capable of transporting a wide range of purine and pyrimidine nucleobases, nucleosides and nucleotides, with cGMP, 2'deoxyguanosine and GMP being the preferred substrates. Functions as a pH- and chloride-independent cGMP bidirectional facilitative transporter that can regulate both intracellular and extracellular levels of cGMP and may be involved in cGMP signaling pathways. Mediates orotate/glutamate bidirectional exchange and most likely display a physiological role in hepatic release of glutamate into the blood. Involved in renal secretion and possible reabsorption of creatinine. Able to uptake prostaglandin E2 (PGE2) and may contribute to PGE2 renal excretion (Probable). Also transports alpha-ketoglutarate and urate. Apart from the orotate/glutamate exchange, the counterions for the uptake of other SLC22A7/OAT2 substrates remain to be identified ; [Isoform 1]: Non functional transporter; [Isoform 3]: Involved in the uptake of prostaglandin F2-alpha (PGF2-alpha).
• Tissue Specificity: Mainly expressed in liver and kidney . In kidney, expressed in proximal tubular cells . Also expressed in pancreas, small intestine, spinal cord, lung, brain and heart . Expressed in fetal liver .
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway:
  Aspirin ADME (R-HSA-9749641)
  Organic anion transport (R-HSA-561048)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 15 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Fluorouracil.	[13]
Paclitaxel	DMLB81S	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Paclitaxel.	[13]
Vitamin C	DMXJ7O8	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Vitamin C.	[13]
Dinoprostone	DMTYOPD	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Dinoprostone.	[13]
Tetracycline	DMZA017	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Tetracycline.	[13]
Cimetidine	DMH61ZB	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the uptake of Cimetidine.	[14]
Allopurinol	DMLPAOB	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Allopurinol.	[13]
Ranitidine	DM0GUSX	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the uptake of Ranitidine.	[14]
Dehydroepiandrosterone sulfate	DM4Q80H	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Dehydroepiandrosterone sulfate.	[13]
Bumetanide	DMRV7H0	Approved	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Bumetanide.	[13]
PGF2alpha	DM4XAU7	Clinical trial	Solute carrier family 22 member 7 (SLC22A7) increases the uptake of PGF2alpha.	[13]
Aminohippuric acid	DMUN54G	Investigative	Solute carrier family 22 member 7 (SLC22A7) increases the uptake of Aminohippuric acid.	[13]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier family 22 member 7 (SLC22A7) increases the uptake of [3H]estrone-3-sulphate.	[13]
Glutarate	DMPUFDS	Investigative	Solute carrier family 22 member 7 (SLC22A7) increases the transport of Glutarate.	[13]
Orotic acid	DMP6BSH	Investigative	Solute carrier family 22 member 7 (SLC22A7) increases the export of Orotic acid.	[15]

26 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 7 (SLC22A7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Solute carrier family 22 member 7 (SLC22A7).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[5]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Piroxicam	DMTK234	Approved	Piroxicam decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[5]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Solute carrier family 22 member 7 (SLC22A7).	[8]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[9]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Solute carrier family 22 member 7 (SLC22A7).	[10]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Ketoprofen	DMRKXPT	Approved	Ketoprofen decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Salicyclic acid	DM2F8XZ	Approved	Salicyclic acid decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[2]
PMID26560530-Compound-34	DMLGZPO	Patented	PMID26560530-Compound-34 decreases the expression of Solute carrier family 22 member 7 (SLC22A7).	[5]
Phenacetin	DMRQAM0	Withdrawn from market	Phenacetin decreases the activity of Solute carrier family 22 member 7 (SLC22A7).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Solute carrier family 22 member 7 (SLC22A7).	[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] 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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [5] Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos. 2006 Oct;34(10):1756-63. doi: 10.1124/dmd.106.010033. Epub 2006 Jul 12.
• [6] 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.
• [7] 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.
• [8] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [9] 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.
• [10] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [13] Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol. 2005 May;57(5):573-8.
• [14] 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.
• [15] Benzoic acid and specific 2-oxo acids activate hepatic efflux of glutamate at OAT2. Biochim Biophys Acta. 2013 Feb;1828(2):491-8. doi: 10.1016/j.bbamem.2012.08.026. Epub 2012 Sep 7.