Details of Drug Off-Target (DOT)

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

• DOT Name: Solute carrier family 22 member 11 (SLC22A11)
• Synonyms: Organic anion transporter 4; OAT4; Organic anion:dicarboxylate exchanger OAT4
• Gene Name: SLC22A11
• UniProt ID: S22AB_HUMAN
• Pfam ID: PF00083
• Sequence:
  MAFSKLLEQAGGVGLFQTLQVLTFILPCLMIPSQMLLENFSAAIPGHRCWTHMLDNGSAV
  STNMTPKALLTISIPPGPNQGPHQCRRFRQPQWQLLDPNATATSWSEADTEPCVDGWVYD
  RSVFTSTIVAKWDLVCSSQGLKPLSQSIFMSGILVGSFIWGLLSYRFGRKPMLSWCCLQL
  AVAGTSTIFAPTFVIYCGLRFVAAFGMAGIFLSSLTLMVEWTTTSRRAVTMTVVGCAFSA
  GQAALGGLAFALRDWRTLQLAASVPFFAISLISWWLPESARWLIIKGKPDQALQELRKVA
  RINGHKEAKNLTIEVLMSSVKEEVASAKEPRSVLDLFCVPVLRWRSCAMLVVNFSLLISY
  YGLVFDLQSLGRDIFLLQALFGAVDFLGRATTALLLSFLGRRTIQAGSQAMAGLAILANM
  LVPQDLQTLRVVFAVLGKGCFGISLTCLTIYKAELFPTPVRMTADGILHTVGRLGAMMGP
  LILMSRQALPLLPPLLYGVISIASSLVVLFFLPETQGLPLPDTIQDLESQKSTAAQGNRQ
  EAVTVESTSL
• Function: Antiporter that mediates the transport of conjugated steroids and other specific organic anions at the basal membrane of syncytiotrophoblast and at the apical membrane of proximal tubule epithelial cells, in exchange for anionic compounds. May be responsible for placental absorption of fetal-derived steroid sulfates such as estrone sulfate (E1S) and the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S), as well as clearing waste products and xenobiotics from the fetus. Maybe also be involved in placental urate homeostasis. Facilitates the renal reabsorption of organic anions such as urate and derived steroid sulfates. Organic anion glutarate acts as conteranion for E1S renal uptake. Possible transport mode may also include DHEA-S/E1S exchange. Also interacts with inorganic anions such as chloride and hydroxyl ions, therefore possible transport modes may include E1S/Cl(-), E1S/OH(-), urate/Cl(-) and urate/OH(-). Also mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion. Also able to uptake anionic drugs, diuretics, bile salts and ochratoxin A. Mediates the unidirectional efflux of glutamate and aspartate. Glutamate efflux down its transmembrane gradient may drive SLC22A11/OAT4-mediated placental uptake of E1S.
• Tissue Specificity: Expressed in placental trophoblasts, syncytiotrophoblast and cytotrophoblast . Also located in the proximal tubules in kidneys .
• Reactome Pathway: Organic anion transport (R-HSA-561048)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dehydroepiandrosterone sulfate	DM4Q80H	Approved	Solute carrier family 22 member 11 (SLC22A11) affects the transport of Dehydroepiandrosterone sulfate.	[10]
Enalaprilat	DMFYAM1	Approved	Solute carrier family 22 member 11 (SLC22A11) increases the uptake of Enalaprilat.	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	Solute carrier family 22 member 11 (SLC22A11) affects the transport of 3R14S-OCHRATOXIN A.	[10]
Aminohippuric acid	DMUN54G	Investigative	Solute carrier family 22 member 11 (SLC22A11) increases the export of Aminohippuric acid.	[12]
Daidzein	DMRFTJX	Investigative	Solute carrier family 22 member 11 (SLC22A11) increases the transport of Daidzein.	[13]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier family 22 member 11 (SLC22A11) increases the import of [3H]estrone-3-sulphate.	[14]
6-Carboxyfluorescein	DMWTMDH	Investigative	Solute carrier family 22 member 11 (SLC22A11) increases the import of 6-Carboxyfluorescein.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Solute carrier family 22 member 11 (SLC22A11).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Solute carrier family 22 member 11 (SLC22A11).	[4]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Solute carrier family 22 member 11 (SLC22A11).	[5]
Aspirin	DM672AH	Approved	Aspirin decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Piroxicam	DMTK234	Approved	Piroxicam decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Ketoprofen	DMRKXPT	Approved	Ketoprofen decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Salicyclic acid	DM2F8XZ	Approved	Salicyclic acid decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]
Probenecid	DMMFWOJ	Approved	Probenecid decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Solute carrier family 22 member 11 (SLC22A11).	[7]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Solute carrier family 22 member 11 (SLC22A11).	[8]
Phenacetin	DMRQAM0	Withdrawn from market	Phenacetin decreases the activity of Solute carrier family 22 member 11 (SLC22A11).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Solute carrier family 22 member 11 (SLC22A11).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Solute carrier family 22 member 11 (SLC22A11).	[9]

References

• [1] 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.
• [2] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [3] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [4] Multiple drug transporters mediate the placental transport of sulpiride. Arch Toxicol. 2017 Dec;91(12):3873-3884. doi: 10.1007/s00204-017-2008-8. Epub 2017 Jun 9.
• [5] 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.
• [6] Neonicotinoid pesticides poorly interact with human drug transporters. J Biochem Mol Toxicol. 2019 Oct;33(10):e22379. doi: 10.1002/jbt.22379. Epub 2019 Jul 31.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000 Feb 11;275(6):4507-12.
• [11] Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule. Pharmaceutics. 2020 Sep 30;12(10):935. doi: 10.3390/pharmaceutics12100935.
• [12] Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy. Toxicology. 2009 Oct 1;264(1-2):74-9. doi: 10.1016/j.tox.2009.07.014. Epub 2009 Jul 28.
• [13] Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1. Arch Toxicol. 2015 Dec;89(12):2253-63. doi: 10.1007/s00204-014-1379-3. Epub 2014 Oct 16.
• [14] Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates. Toxicol Sci. 2010 Oct;117(2):294-302. doi: 10.1093/toxsci/kfq219. Epub 2010 Jul 16.