Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTERJ4VQ)

• DOT Name: Solute carrier organic anion transporter family member 2B1 (SLCO2B1)
• Synonyms: Organic anion transporter B; OATP-B; Organic anion transporter polypeptide-related protein 2; OATP-RP2; OATPRP2; Organic anion transporting polypeptide 2B1; OATP2B1; Solute carrier family 21 member 9
• Gene Name: SLCO2B1
• UniProt ID: SO2B1_HUMAN
• Pfam ID: PF03137
• Sequence:
  MGPRIGPAGEVPQVPDKETKATMGTENTPGGKASPDPQDVRPSVFHNIKLFVLCHSLLQL
  AQLMISGYLKSSISTVEKRFGLSSQTSGLLASFNEVGNTALIVFVSYFGSRVHRPRMIGY
  GAILVALAGLLMTLPHFISEPYRYDNTSPEDMPQDFKASLCLPTTSAPASAPSNGNCSSY
  TETQHLSVVGIMFVAQTLLGVGGVPIQPFGISYIDDFAHNSNSPLYLGILFAVTMMGPGL
  AFGLGSLMLRLYVDINQMPEGGISLTIKDPRWVGAWWLGFLIAAGAVALAAIPYFFFPKE
  MPKEKRELQFRRKVLAVTDSPARKGKDSPSKQSPGESTKKQDGLVQIAPNLTVIQFIKVF
  PRVLLQTLRHPIFLLVVLSQVCLSSMAAGMATFLPKFLERQFSITASYANLLIGCLSFPS
  VIVGIVVGGVLVKRLHLGPVGCGALCLLGMLLCLFFSLPLFFIGCSSHQIAGITHQTSAH
  PGLELSPSCMEACSCPLDGFNPVCDPSTRVEYITPCHAGCSSWVVQDALDNSQVFYTNCS
  CVVEGNPVLAGSCDSTCSHLVVPFLLLVSLGSALACLTHTPSFMLILRGVKKEDKTLAVG
  IQFMFLRILAWMPSPVIHGSAIDTTCVHWALSCGRRAVCRYYNNDLLRNRFIGLQFFFKT
  GSVICFALVLAVLRQQDKEARTKESRSSPAVEQQLLVSGPGKKPEDSRV
• Function: Mediates the Na(+)-independent transport of steroid sulfate conjugates and other specific organic anions. Responsible for the transport of estrone 3-sulfate (E1S) through the basal membrane of syncytiotrophoblast, highlighting a potential role in the placental absorption of fetal-derived sulfated steroids including the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S). Also facilitates the uptake of sulfated steroids at the basal/sinusoidal membrane of hepatocytes, therefore accounting for the major part of organic anions clearance of liver. Mediates the intestinal uptake of sulfated steroids. Mediates the uptake of the neurosteroids DHEA-S and pregnenolone sulfate (PregS) into the endothelial cells of the blood-brain barrier as the first step to enter the brain. Also plays a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons. May act as a heme transporter that promotes cellular iron availability via heme oxygenase/HMOX2 and independently of TFRC. Also transports heme by-product coproporphyrin III (CPIII), and may be involved in their hepatic disposition. Mediates the uptake of other substrates such as prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), taurocholate, L-thyroxine, leukotriene C4 and thromboxane B2. May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). 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. The exact transport mechanism has not been yet deciphered but most likely involves an anion exchange, coupling the cellular uptake of organic substrate with the efflux of an anionic compound. Hydrogencarbonate/HCO3(-) acts as a probable counteranion that exchanges for organic anions. Cytoplasmic glutamate may also act as counteranion in the placenta. An inwardly directed proton gradient has also been proposed as the driving force of E1S uptake with a (H(+):E1S) stoichiometry of (1:1) ; [Isoform 3]: Has estrone 3-sulfate (E1S) transport activity comparable with the full-length isoform 1.
• Tissue Specificity: Strongly expressed in the liver, at the sinusoidal membrane of the hepatocytes . Expressed in the kidney . Expressed in placental trophoblasts and syncytiotrophoblast . Expressed in the small intestine . Expressed in the blood-brain barrier, in endothelial cells of brain capillaries . Expressed in the retina, in the inner nuclear layer and the inner plexiform layer . Expressed in skelettal muscles . In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed within the tubules . Also expressed in pancreas, lung, heart, colon, ovary and spleen . Expressed in fetal brain, heart, kidney, liver, lung, skeletal muscle, spleen and pancreas .; [Isoform 1]: Highest expression in brain. Predominant isoform compared to isoform 3 in small intestine duodenum, kidney, placenta, and skeletal muscle.; [Isoform 3]: Predominant isoform compared to isoform 1 in liver. Also expressed in small intestine duodenum, kidney, brain, placenta, and skeletal muscle.
• Reactome Pathway:
  (Name not found)
  Transport of organic anions (R-HSA-879518)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 10 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the transport of Arsenic.	[5]
Quercetin	DM3NC4M	Approved	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of Quercetin.	[22]
Cholic acid	DM7OKQV	Approved	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of Cholic acid.	[21]
Atorvastatin	DMF28YC	Phase 3 Trial	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of Atorvastatin.	[23]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of Amiodarone.	[24]
Taurocholic acid	DM2LZ8F	Phase 1/2	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of Taurocholic acid.	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of 3R14S-OCHRATOXIN A.	[25]
Daidzein	DMRFTJX	Investigative	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the transport of Daidzein.	[26]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the import of [3H]estrone-3-sulphate.	[27]
Asacolitin	DM3WVPJ	Investigative	Solute carrier organic anion transporter family member 2B1 (SLCO2B1) increases the uptake of Asacolitin.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[12]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[15]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[12]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[12]
Meclizine	DMS7T13	Approved	Meclizine increases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[16]
ICARIIN	DMOJQGT	Phase 3	ICARIIN decreases the activity of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[19]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[20]

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 decreases the methylation of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Rutin	DMEHRAJ	Investigative	Rutin affects the localization of Solute carrier organic anion transporter family member 2B1 (SLCO2B1).	[21]

References

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• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] In vitro study of transporters involved in intestinal absorption of inorganic arsenic. Chem Res Toxicol. 2012 Feb 20;25(2):446-53. doi: 10.1021/tx200491f. Epub 2012 Jan 26.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] 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.
• [12] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [13] Prenatal ethanol exposure increases maternal bile acids through placental transport pathway. Toxicology. 2021 Jun 30;458:152848. doi: 10.1016/j.tox.2021.152848. Epub 2021 Jul 2.
• [14] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Interaction of the bioactive flavonol, icariin, with the essential human solute carrier transporters. J Biochem Mol Toxicol. 2014 Feb;28(2):91-7. doi: 10.1002/jbt.21540. Epub 2013 Nov 21.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Quercetin-3-rhamnoglucoside (rutin) stimulates transport of organic anion compounds mediated by organic anion transporting polypeptide 2B1. Biopharm Drug Dispos. 2014 Apr;35(3):173-82. doi: 10.1002/bdd.1882. Epub 2014 Jan 14.
• [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] The influence of oral antidiabetic drugs on cellular drug uptake mediated by hepatic OATP family members. Basic Clin Pharmacol Toxicol. 2013 Apr;112(4):244-50. doi: 10.1111/bcpt.12031. Epub 2012 Dec 6.
• [24] Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells. Biochim Biophys Acta. 2009 May;1788(5):911-7. doi: 10.1016/j.bbamem.2009.03.003. Epub 2009 Mar 11.
• [25] 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.
• [26] 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.
• [27] Predominant contribution of organic anion transporting polypeptide OATP-B (OATP2B1) to apical uptake of estrone-3-sulfate by human intestinal Caco-2 cells. Drug Metab Dispos. 2006 Aug;34(8):1423-31.
• [28] Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos. 2011 Jun;39(6):1097-102.