Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4WYPSR)

• DOT Name: Organic solute transporter subunit beta (SLC51B)
• Synonyms: OST-beta; Solute carrier family 51 subunit beta
• Gene Name: SLC51B
• Related Disease: Bile acid malabsorption, primary, 2
• UniProt ID: OSTB_HUMAN
• Pfam ID: PF15048
• Sequence:
  MEHSEGAPGDPAGTVVPQELLEEMLWFFRVEDASPWNHSILALAAVVVIISMVLLGRSIQ
  ASRKEKMQPPEKETPEVLHLDEAKDHNSLNNLRETLLSEKPNLAQVELELKERDVLSVFL
  PDVPETES
• Function: Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood. Modulates SLC51A glycosylation, membrane trafficking and stability activities. The Ost-alpha/Ost-beta complex efficiently transports the major species of bile acids (taurocholate). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids. Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols. Able to transport eicosanoids such as prostaglandin E2.
• Tissue Specificity: Widely expressed with a high expression in ileum. Expressed in testis, colon, liver, small intestine, kidney, ovary and adrenal gland; and at low levels in heart, lung, brain, pituitary, thyroid gland, uterus, prostate, mammary gland and fat.
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway: 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
Bile acid malabsorption, primary, 2	DIS3GU4D	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Organic solute transporter subunit beta (SLC51B).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Organic solute transporter subunit beta (SLC51B).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Organic solute transporter subunit beta (SLC51B).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Organic solute transporter subunit beta (SLC51B).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Organic solute transporter subunit beta (SLC51B).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Organic solute transporter subunit beta (SLC51B).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Organic solute transporter subunit beta (SLC51B).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Organic solute transporter subunit beta (SLC51B).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Organic solute transporter subunit beta (SLC51B).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Organic solute transporter subunit beta (SLC51B).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Organic solute transporter subunit beta (SLC51B).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Organic solute transporter subunit beta (SLC51B).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Organic solute transporter subunit beta (SLC51B).	[13]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Organic solute transporter subunit beta (SLC51B).	[14]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Organic solute transporter subunit beta (SLC51B).	[15]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the expression of Organic solute transporter subunit beta (SLC51B).	[16]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Organic solute transporter subunit beta (SLC51B).	[17]
Bosentan	DMIOGBU	Approved	Bosentan increases the expression of Organic solute transporter subunit beta (SLC51B).	[18]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of Organic solute transporter subunit beta (SLC51B).	[16]
Budesonide	DMJIBAW	Approved	Budesonide increases the expression of Organic solute transporter subunit beta (SLC51B).	[9]
Pantothenic acid	DM091H2	Approved	Pantothenic acid increases the expression of Organic solute transporter subunit beta (SLC51B).	[19]
Cholic acid	DM7OKQV	Approved	Cholic acid increases the expression of Organic solute transporter subunit beta (SLC51B).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Organic solute transporter subunit beta (SLC51B).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Organic solute transporter subunit beta (SLC51B).	[23]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Organic solute transporter subunit beta (SLC51B).	[24]
	DM9CEI5		increases the expression of Organic solute transporter subunit beta (SLC51B).	[9]

2 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 increases the methylation of Organic solute transporter subunit beta (SLC51B).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Organic solute transporter subunit beta (SLC51B).	[22]

References

• [1] Organic solute transporter- (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis. Hepatology. 2018 Aug;68(2):590-598. doi: 10.1002/hep.29516. Epub 2018 May 11.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos. 2009 Jul;30(5):241-58.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] 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.
• [13] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [14] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [15] Similarities and differences between two modes of antagonism of the thyroid hormone receptor. ACS Chem Biol. 2011 Oct 21;6(10):1096-106.
• [16] 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.
• [17] Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1124-30. doi: 10.1152/ajpgi.00539.2005. Epub 2006 Jan 19.
• [18] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [19] Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] 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.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.