Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO70C5O)

• DOT Name: Solute carrier organic anion transporter family member 1A2 (SLCO1A2)
• Synonyms: OATP1A2; OATP-A; Organic anion-transporting polypeptide 1; OATP-1; Sodium-independent organic anion transporter; Solute carrier family 21 member 3
• Gene Name: SLCO1A2
• UniProt ID: SO1A2_HUMAN
• Pfam ID: PF07648 ; PF03137
• Sequence:
  MGETEKRIETHRIRCLSKLKMFLLAITCAFVSKTLSGSYMNSMLTQIERQFNIPTSLVGF
  INGSFEIGNLLLIIFVSYFGTKLHRPIMIGIGCVVMGLGCFLKSLPHFLMNQYEYESTVS
  VSGNLSSNSFLCMENGTQILRPTQDPSECTKEVKSLMWVYVLVGNIVRGMGETPILPLGI
  SYIEDFAKFENSPLYIGLVETGAIIGPLIGLLLASFCANVYVDTGFVNTDDLIITPTDTR
  WVGAWWFGFLICAGVNVLTAIPFFFLPNTLPKEGLETNADIIKNENEDKQKEEVKKEKYG
  ITKDFLPFMKSLSCNPIYMLFILVSVIQFNAFVNMISFMPKYLEQQYGISSSDAIFLMGI
  YNLPPICIGYIIGGLIMKKFKITVKQAAHIGCWLSLLEYLLYFLSFLMTCENSSVVGINT
  SYEGIPQDLYVENDIFADCNVDCNCPSKIWDPVCGNNGLSYLSACLAGCETSIGTGINMV
  FQNCSCIQTSGNSSAVLGLCDKGPDCSLMLQYFLILSAMSSFIYSLAAIPGYMVLLRCMK
  SEEKSLGVGLHTFCTRVFAGIPAPIYFGALMDSTCLHWGTLKCGESGACRIYDSTTFRYI
  YLGLPAALRGSSFVPALIILILLRKCHLPGENASSGTELIETKVKGKENECKDIYQKSTV
  LKDDELKTKL
• Function: Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane. Responsible for intestinal absorption of bile acids. Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision. Involved in the uptake of clinically used drugs. Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine). Also transports prostaglandin E2. Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells. May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons. May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel. Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment. Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions. May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable).
• Tissue Specificity: Higher expression in the brain than in liver and kidney . Expressed in brain neurons in both cortex and hippocampus . Expressed in placental trophoblasts . Also expressed in lung and testes at lower levels . Expressed in the eye (at protein level) . Expressed in the retina in the outer and inner nuclear layers, the inner plexiform layer and the ganglion cell layer . Expressed in liver and prostate . In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and within the tubules . Expressed in fetal brain and liver .
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway:
  Transport of organic anions (R-HSA-879518)
  Ciprofloxacin ADME (R-HSA-9793528)
  Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 8 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) increases the uptake of Quercetin.	[13]
Hydroxyurea	DMOQVU9	Approved	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) increases the uptake of Hydroxyurea.	[14]
Quinine	DMSWYF5	Approved	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) increases the uptake of Quinine.	[15]
Saquinavir	DMG814N	Approved	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) affects the uptake of Saquinavir.	[16]
Trospium chloride	DM32XZT	Approved	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) increases the metabolism of Trospium chloride.	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) increases the uptake of 3R14S-OCHRATOXIN A.	[18]
3-iodothyronamine	DM3L0F8	Investigative	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) affects the uptake of 3-iodothyronamine.	[19]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier organic anion transporter family member 1A2 (SLCO1A2) increases the import of [3H]estrone-3-sulphate.	[20]

12 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 organic anion transporter family member 1A2 (SLCO1A2).	[1]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[3]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[4]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[5]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[6]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[7]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[8]
Omeprazole	DM471KJ	Approved	Omeprazole increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[10]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[12]
pregnenolone-16alpha-carbonitrile	DM0LW7G	Investigative	pregnenolone-16alpha-carbonitrile increases the expression of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[9]

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 affects the methylation of Solute carrier organic anion transporter family member 1A2 (SLCO1A2).	[11]

References

• [1] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [2] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [3] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [4] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [5] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [6] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [7] UDCA and CDCA alleviate 17-ethinylestradiol-induced cholestasis through PKA-AMPK pathways in rats. Toxicol Appl Pharmacol. 2016 Nov 15;311:12-25. doi: 10.1016/j.taap.2016.10.011. Epub 2016 Oct 12.
• [8] The SLCO1A2 gene, encoding human organic anion-transporting polypeptide 1A2, is transactivated by the vitamin D receptor. Mol Pharmacol. 2012 Jul;82(1):37-46. doi: 10.1124/mol.112.077909. Epub 2012 Apr 3.
• [9] Use of mRNA expression to detect the induction of drug metabolising enzymes in rat and human hepatocytes. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):86-96.
• [10] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [11] 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.
• [12] Comparison of long-term versus short-term effects of okadaic acid on the apoptotic status of human HepaRG cells. Chem Biol Interact. 2020 Feb 1;317:108937. doi: 10.1016/j.cbi.2020.108937. Epub 2020 Jan 8.
• [13] 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.
• [14] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.
• [15] Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy. Drug Metab Dispos. 2016 Oct;44(10):1562-8. doi: 10.1124/dmd.116.069807. Epub 2016 Aug 8.
• [16] Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of Saquinavir in Hep G2 cells. Mol Pharm. 2004 Jan 12;1(1):49-56.
• [17] Expression of drug transporters and drug metabolizing enzymes in the bladder urothelium in man and affinity of the bladder spasmolytic trospium chloride to transporters likely involved in its pharmacokinetics. Mol Pharm. 2015 Jan 5;12(1):171-8.
• [18] Ochratoxin A transport by the human breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), and organic anion-transporting polypeptides 1A2, 1B1 and 2B1. Toxicol Appl Pharmacol. 2017 Aug 15;329:18-25. doi: 10.1016/j.taap.2017.05.022. Epub 2017 May 19.
• [19] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.
• [20] Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther. 2006 Aug;318(2):521-9.