Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3062CA)

• DOT Name: Solute carrier organic anion transporter family member 2A1 (SLCO2A1)
• Synonyms: SLCO2A1; OATP2A1; PHOAR2; Prostaglandin transporter; PGT; Solute carrier family 21 member 2; SLC21A2
• Gene Name: SLCO2A1
• Related Disease:
  Hypertrophic osteoarthropathy, primary, autosomal dominant
  Hypertrophic osteoarthropathy, primary, autosomal recessive, 2
  Chronic enteropathy associated with SLCO2A1 gene
  Obsolete pachydermoperiostosis
• UniProt ID: SO2A1_HUMAN
• PDB ID: 3MRR
• Pfam ID: PF07648 ; PF03137
• Sequence:
  MGLLPKLGASQGSDTSTSRAGRCARSVFGNIKVFVLCQGLLQLCQLLYSAYFKSSLTTIE
  KRFGLSSSSSGLISSLNEISNAILIIFVSYFGSRVHRPRLIGIGGLFLAAGAFILTLPHF
  LSEPYQYTLASTGNNSRLQAELCQKHWQDLPPSKCHSTTQNPQKETSSMWGLMVVAQLLA
  GIGTVPIQPFGISYVDDFSEPSNSPLYISILFAISVFGPAFGYLLGSVMLQIFVDYGRVN
  TAAVNLVPGDPRWIGAWWLGLLISSALLVLTSFPFFFFPRAMPIGAKRAPATADEARKLE
  EAKSRGSLVDFIKRFPCIFLRLLMNSLFVLVVLAQCTFSSVIAGLSTFLNKFLEKQYGTS
  AAYANFLIGAVNLPAAALGMLFGGILMKRFVFSLQAIPRIATTIITISMILCVPLFFMGC
  STPTVAEVYPPSTSSSIHPQSPACRRDCSCPDSIFHPVCGDNGIEYLSPCHAGCSNINMS
  SATSKQLIYLNCSCVTGGSASAKTGSCPVPCAHFLLPAIFLISFVSLIACISHNPLYMMV
  LRVVNQEEKSFAIGVQFLLMRLLAWLPSPALYGLTIDHSCIRWNSLCLGRRGACAYYDND
  ALRDRYLGLQMGYKALGMLLLCFISWRVKKNKEYNVQKAAGLI
• Function: Mediates the transport of prostaglandins (PGs, mainly PGE2, PGE1, PGE3, PGF2alpha, PGD2, PGH2) and thromboxanes (thromboxane B2) across the cell membrane. PGs and thromboxanes play fundamental roles in diverse functions such as intraocular pressure, gastric acid secretion, renal salt and water transport, vascular tone, and fever. Plays a role in the clearance of PGs from the circulation through cellular uptake, which allows cytoplasmic oxidation and PG signal termination. PG uptake is dependent upon membrane potential and involves exchange of a monovalent anionic substrate (PGs exist physiologically as an anionic monovalent form) with a stoichiometry of 1:1 for divalent anions or of 1:2 for monovalent anions. Uses lactate, generated by glycolysis, as a counter-substrate to mediate PGE2 influx and efflux. Under nonglycolytic conditions, metabolites other than lactate might serve as counter-substrates. Although the mechanism is not clear, this transporter can function in bidirectional mode. When apically expressed in epithelial cells, it facilitates transcellular transport (also called vectorial release), extracting PG from the apical medium and facilitating transport across the cell toward the basolateral side, whereupon the PG exits the cell by simple diffusion. In the renal collecting duct, regulates renal Na+ balance by removing PGE2 from apical medium (PGE2 EP4 receptor is likely localized to the luminal/apical membrane and stimulates Na+ resorption) and transporting it toward the basolateral membrane (where PGE2 EP1 and EP3 receptors inhibit Na+ resorption). Plays a role in endometrium during decidualization, increasing uptake of PGs by decidual cells. Involved in critical events for ovulation. Regulates extracellular PGE2 concentration for follicular development in the ovaries. Expressed intracellularly, may contribute to vesicular uptake of newly synthesized intracellular PGs, thereby facilitating exocytotic secretion of PGs without being metabolized. Essential core component of the major type of large-conductance anion channel, Maxi-Cl, which plays essential roles in inorganic anion transport, cell volume regulation and release of ATP and glutamate not only in physiological processes but also in pathological processes. May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable).
• Tissue Specificity: Ubiquitous . Significant expression observed in lung, kidney, spleen, and heart . Expressed in the endometrium (at both mRNA and protein levels) . Expressed in the ovaries (at mRNA and protein levels) . In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed within the tubules .
• Reactome Pathway:
  Transport of organic anions (R-HSA-879518)
  Defective SLCO2A1 causes primary, autosomal recessive hypertrophic osteoarthropathy 2 (PHOAR2) (R-HSA-5619095)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypertrophic osteoarthropathy, primary, autosomal dominant	DISXBT1T	Definitive	Autosomal dominant	[1]
Hypertrophic osteoarthropathy, primary, autosomal recessive, 2	DISIGR8N	Definitive	Autosomal recessive	[1]
Chronic enteropathy associated with SLCO2A1 gene	DISULBHG	Supportive	Autosomal recessive	[2]
Obsolete pachydermoperiostosis	DIS1R4Y4	Supportive	Autosomal recessive	[3]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Solute carrier organic anion transporter family member 2A1 (SLCO2A1) increases the uptake of Quercetin.	[22]
Dinoprostone	DMTYOPD	Approved	Solute carrier organic anion transporter family member 2A1 (SLCO2A1) increases the transport of Dinoprostone.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[14]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[15]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Solute carrier organic anion transporter family member 2A1 (SLCO2A1).	[21]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter. PLoS Genet. 2015 Nov 5;11(11):e1005581. doi: 10.1371/journal.pgen.1005581. eCollection 2015 Nov.
• [3] Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. Am J Hum Genet. 2012 Jan 13;90(1):125-32. doi: 10.1016/j.ajhg.2011.11.019. Epub 2011 Dec 22.
• [4] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] Transporter gene expression in human head and neck squamous cell carcinoma and associated epigenetic regulatory mechanisms. Am J Pathol. 2013 Jan;182(1):234-43. doi: 10.1016/j.ajpath.2012.09.008. Epub 2012 Nov 6.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [13] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [14] 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.
• [15] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [16] 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.
• [17] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [22] 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.
• [23] Influence of cyclooxygenase inhibitors on the function of the prostaglandin transporter organic anion-transporting polypeptide 2A1 expressed in human gastroduodenal mucosa. J Pharmacol Exp Ther. 2010 Feb;332(2):345-51. doi: 10.1124/jpet.109.154518. Epub 2009 Oct 20.