Details of Drug Off-Target (DOT)

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

• DOT Name: Hepatic sodium/bile acid cotransporter (SLC10A1)
• Synonyms: Cell growth-inhibiting gene 29 protein; Na(+)/bile acid cotransporter; Na(+)/taurocholate transport protein; Sodium/taurocholate cotransporting polypeptide; NTCP; Solute carrier family 10 member 1; SLC10A1
• Gene Name: SLC10A1
• Related Disease: Hypercholanemia, familial, 2
• UniProt ID: NTCP_HUMAN
• PDB ID: 7FCI; 7PQG; 7PQQ; 7VAD; 7VAG; 7WSI; 7ZYI
• Pfam ID: PF01758
• Sequence:
  MEAHNASAPFNFTLPPNFGKRPTDLALSVILVFMLFFIMLSLGCTMEFSKIKAHLWKPKG
  LAIALVAQYGIMPLTAFVLGKVFRLKNIEALAILVCGCSPGGNLSNVFSLAMKGDMNLSI
  VMTTCSTFCALGMMPLLLYIYSRGIYDGDLKDKVPYKGIVISLVLVLIPCTIGIVLKSKR
  PQYMRYVIKGGMIIILLCSVAVTVLSAINVGKSIMFAMTPLLIATSSLMPFIGFLLGYVL
  SALFCLNGRCRRTVSMETGCQNVQLCSTILNVAFPPEVIGPLFFFPLLYMIFQLGEGLLL
  IAIFWCYEKFKTPKDKTKMIYTAATTEETIPGALGNGTYKGEDCSPCTA
• Function: As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins. It is strictly dependent on the extracellular presence of sodium. It exhibits broad substrate specificity and transports various bile acids, such as taurocholate, cholate, as well as non-bile acid organic compounds, such as estrone sulfate. Works collaboratively with the ileal transporter (NTCP2), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation ; (Microbial infection) Acts as a receptor for hepatitis B virus.
• Tissue Specificity: Expressed in liver . Expressed in placental trophoblasts .
• KEGG Pathway:
  Bile secretion (hsa04976)
  Hepatitis B (hsa05161)
• 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
Hypercholanemia, familial, 2	DIS8AK5G	Limited	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daidzein	DMRFTJX	Investigative	Hepatic sodium/bile acid cotransporter (SLC10A1) increases the transport of Daidzein.	[26]

35 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 Hepatic sodium/bile acid cotransporter (SLC10A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[10]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[11]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[12]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[13]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[14]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[8]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[15]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[16]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[17]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[18]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[19]
Atazanavir	DMSYRBX	Approved	Atazanavir decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[17]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[20]
Salbutamol	DMN9CWF	Approved	Salbutamol increases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[21]
Cholic acid	DM7OKQV	Approved	Cholic acid decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[18]
Tolvaptan	DMIWFRL	Approved	Tolvaptan decreases the activity of Hepatic sodium/bile acid cotransporter (SLC10A1).	[22]
Macitentan	DMP79A1	Approved	Macitentan decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[19]
TAK-875	DMIM5AP	Phase 3	TAK-875 decreases the activity of Hepatic sodium/bile acid cotransporter (SLC10A1).	[23]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[3]
PMID26560530-Compound-34	DMLGZPO	Patented	PMID26560530-Compound-34 decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[8]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[20]
Icariside II	DM3DB8X	Investigative	Icariside II increases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[25]
chlordane	DMMHU8G	Investigative	chlordane decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[15]
Ro 41-5253	DMSJLWP	Investigative	Ro 41-5253 decreases the expression of Hepatic sodium/bile acid cotransporter (SLC10A1).	[4]

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] 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.
• [4] Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression. J Biol Chem. 2015 Feb 27;290(9):5673-84. doi: 10.1074/jbc.M114.602540. Epub 2014 Dec 30.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [8] 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.
• [9] Development of stably transfected human and rat hepatoma cell lines for the species-specific assessment of xenobiotic response enhancer module (XREM)-dependent induction of drug metabolism. Toxicology. 2010 Nov 9;277(1-3):11-9.
• [10] 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.
• [11] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [12] 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.
• [13] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [14] The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol Pharmacol. 2005 Aug;68(2):551-8. doi: 10.1124/mol.105.012104. Epub 2005 May 23.
• [15] Regulation of hepatic drug transporter activity and expression by organochlorine pesticides. J Biochem Mol Toxicol. 2014 Mar;28(3):119-28.
• [16] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [17] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [18] 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.
• [19] From the Cover: MechanisticInsights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells. Toxicol Sci. 2017 Jun 1;157(2):451-464. doi: 10.1093/toxsci/kfx062.
• [20] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [21] Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis. Toxicol Sci. 2023 Nov 28;196(2):200-217. doi: 10.1093/toxsci/kfad088.
• [22] Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?. Toxicol Sci. 2016 Jan;149(1):237-50. doi: 10.1093/toxsci/kfv231. Epub 2015 Oct 26.
• [23] Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury. Toxicol Sci. 2017 May 1;157(1):50-61. doi: 10.1093/toxsci/kfx018.
• [24] The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes. Arch Toxicol. 2018 Mar;92(3):1099-1112.
• [25] Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER degradation. Cell Biol Toxicol. 2023 Aug;39(4):1215-1235. doi: 10.1007/s10565-022-09737-x. Epub 2022 Jul 8.
• [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.