Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOM3BUH)

• DOT Name: Solute carrier organic anion transporter family member 1B3 (SLCO1B3)
• Synonyms: Liver-specific organic anion transporter 2; LST-2; OATP1B3; Organic anion transporter 8; Organic anion-transporting polypeptide 8; OATP-8; Solute carrier family 21 member 8
• Gene Name: SLCO1B3
• Related Disease: Rotor syndrome
• UniProt ID: SO1B3_HUMAN
• PDB ID: 8PG0
• Pfam ID: PF07648 ; PF03137
• Sequence:
  MDQHQHLNKTAESASSEKKKTRRCNGFKMFLAALSFSYIAKALGGIIMKISITQIERRFD
  ISSSLAGLIDGSFEIGNLLVIVFVSYFGSKLHRPKLIGIGCLLMGTGSILTSLPHFFMGY
  YRYSKETHINPSENSTSSLSTCLINQTLSFNGTSPEIVEKDCVKESGSHMWIYVFMGNML
  RGIGETPIVPLGISYIDDFAKEGHSSLYLGSLNAIGMIGPVIGFALGSLFAKMYVDIGYV
  DLSTIRITPKDSRWVGAWWLGFLVSGLFSIISSIPFFFLPKNPNKPQKERKISLSLHVLK
  TNDDRNQTANLTNQGKNVTKNVTGFFQSLKSILTNPLYVIFLLLTLLQVSSFIGSFTYVF
  KYMEQQYGQSASHANFLLGIITIPTVATGMFLGGFIIKKFKLSLVGIAKFSFLTSMISFL
  FQLLYFPLICESKSVAGLTLTYDGNNSVASHVDVPLSYCNSECNCDESQWEPVCGNNGIT
  YLSPCLAGCKSSSGIKKHTVFYNCSCVEVTGLQNRNYSAHLGECPRDNTCTRKFFIYVAI
  QVINSLFSATGGTTFILLTVKIVQPELKALAMGFQSMVIRTLGGILAPIYFGALIDKTCM
  KWSTNSCGAQGACRIYNSVFFGRVYLGLSIALRFPALVLYIVFIFAMKKKFQGKDTKASD
  NERKVMDEANLEFLNNGEHFVPSAGTDSKTCNLDMQDNAAAN
• Function: Mediates the Na(+)-independent uptake of organic anions. Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions. Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment. Involved in the clearance of bile acids and organic anions from the liver. Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop. Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition. May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs. May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel. May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver.
• Tissue Specificity: Highly expressed in liver, in particular at the basolateral membrane of hepatocytes near the central vein . Expressed in the placenta . In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and within the tubules .
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway:
  Heme degradation (R-HSA-189483)
  Defective SLCO1B3 causes hyperbilirubinemia, Rotor type (HBLRR) (R-HSA-5619058)
  Transport of organic anions (R-HSA-879518)
  Atorvastatin ADME (R-HSA-9754706)
  Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rotor syndrome	DISNBRRT	Supportive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 12 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Quercetin.	[20]
Hydroxyurea	DMOQVU9	Approved	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Hydroxyurea.	[21]
Ursodeoxycholic acid	DMCUT21	Approved	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Ursodeoxycholic acid.	[22]
Fexofenadine	DM17ONX	Approved	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Fexofenadine.	[24]
Atorvastatin	DMF28YC	Phase 3 Trial	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Atorvastatin.	[25]
MK-8245	DMG6KXB	Phase 2	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of MK-8245.	[26]
Taurocholic acid	DM2LZ8F	Phase 1/2	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Taurocholic acid.	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the transport of 3R14S-OCHRATOXIN A.	[28]
Microcystin-LR	DMTMLRN	Investigative	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the import of Microcystin-LR.	[30]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of [3H]estrone-3-sulphate.	[31]
Asacolitin	DM3WVPJ	Investigative	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of Asacolitin.	[32]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Investigative	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the uptake of [3H]estradiol-17beta-glucuronide.	[33]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) affects the response to substance of Warfarin.	[23]
Okadaic acid	DM47CO1	Investigative	Solute carrier organic anion transporter family member 1B3 (SLCO1B3) increases the response to substance of Okadaic acid.	[29]

20 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 1B3 (SLCO1B3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[9]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[11]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[12]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[12]
Cholic acid	DM7OKQV	Approved	Cholic acid increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[12]
Trospium chloride	DM32XZT	Approved	Trospium chloride decreases the activity of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[13]
Rifamycin	DMEH3O7	Approved	Rifamycin decreases the activity of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[14]
Fusidic acid	DMWVCF3	Approved	Fusidic acid decreases the activity of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[15]
ICARIIN	DMOJQGT	Phase 3	ICARIIN decreases the activity of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[16]
TAK-875	DMIM5AP	Phase 3	TAK-875 decreases the activity of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[19]
PMID26560530-Compound-34	DMLGZPO	Patented	PMID26560530-Compound-34 decreases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[9]
	DM9CEI5		increases the expression of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[12]

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 organic anion transporter family member 1B3 (SLCO1B3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Solute carrier organic anion transporter family member 1B3 (SLCO1B3).	[18]

References

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• [2] 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.
• [3] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [9] 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.
• [10] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [11] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [12] Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures. Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.
• [13] 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.
• [14] 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.
• [15] Inhibition of Hepatobiliary Transport Activity by the Antibacterial Agent Fusidic Acid: Insights into Factors Contributing to Conjugated Hyperbilirubinemia/Cholestasis. Chem Res Toxicol. 2016 Oct 17;29(10):1778-1788. doi: 10.1021/acs.chemrestox.6b00262. Epub 2016 Oct 4.
• [16] 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.
• [17] Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites. J Biochem Mol Toxicol. 2019 Aug;33(8):e22345. doi: 10.1002/jbt.22345. Epub 2019 May 8.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] 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.
• [21] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.
• [22] Transport of fluorescent chenodeoxycholic acid via the human organic anion transporters OATP1B1 and OATP1B3. J Lipid Res. 2006 Jun;47(6):1196-202.
• [23] Identification of two novel genes SLC15A2 and SLCO1B3 associated with maintenance dose variability of warfarin in a Chinese population. Sci Rep. 2017 Dec 12;7(1):17379. doi: 10.1038/s41598-017-17731-1.
• [24] Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol. 2008 May;73(5):1474-83.
• [25] 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.
• [26] Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. J Med Chem. 2011 Jul 28;54(14):5082-96.
• [27] In vitro inhibition of OATP-mediated uptake of phalloidin using bile acid derivatives. Toxicol Appl Pharmacol. 2009 Aug 15;239(1):13-20. doi: 10.1016/j.taap.2009.04.024. Epub 2009 May 21.
• [28] Human organic anion transporting polypeptide (OATP) 1B3 and mouse OATP1A/1B affect liver accumulation of Ochratoxin A in mice. Toxicol Appl Pharmacol. 2020 Aug 15;401:115072. doi: 10.1016/j.taap.2020.115072. Epub 2020 May 26.
• [29] Okadaic acid is taken-up into the cells mediated by human hepatocytes transporter OATP1B3. Food Chem Toxicol. 2015 Sep;83:229-36. doi: 10.1016/j.fct.2015.06.006. Epub 2015 Jun 29.
• [30] Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3. Toxicol Sci. 2007 Jun;97(2):407-16. doi: 10.1093/toxsci/kfm054. Epub 2007 Mar 16.
• [31] Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S-3100-CA, in mice. Pharmacol Res Perspect. 2021 Oct;9(5):e00877. doi: 10.1002/prp2.877.
• [32] Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos. 2011 Jun;39(6):1097-102.
• [33] Interactions between cyazofamid and human drug transporters. J Biochem Mol Toxicol. 2020 Apr;34(4):e22459. doi: 10.1002/jbt.22459. Epub 2020 Jan 31.