Details of Drug Off-Target (DOT)

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

• DOT Name: Nuclear receptor subfamily 5 group A member 2 (NR5A2)
• Synonyms: Alpha-1-fetoprotein transcription factor; B1-binding factor; hB1F; CYP7A promoter-binding factor; Hepatocytic transcription factor; Liver receptor homolog 1; LRH-1
• Gene Name: NR5A2
• UniProt ID: NR5A2_HUMAN
• PDB ID: 1YOK; 1YUC; 1ZDU; 2A66; 3PLZ; 3TX7; 4DOR; 4DOS; 4IS8; 4ONI; 4PLD; 4PLE; 4RWV; 5L0M; 5L11; 5SYZ; 5UNJ; 6OQX; 6OQY; 6OR1; 6VC2; 6VIF; 7JYD; 7JYE; 7TT8; 8F8M
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MSSNSDTGDLQESLKHGLTPIGAGLPDRHGSPIPARGRLVMLPKVETEALGLARSHGEQG
  QMPENMQVSQFKMVNYSYDEDLEELCPVCGDKVSGYHYGLLTCESCKGFFKRTVQNNKRY
  TCIENQNCQIDKTQRKRCPYCRFQKCLSVGMKLEAVRADRMRGGRNKFGPMYKRDRALKQ
  QKKALIRANGLKLEAMSQVIQAMPSDLTISSAIQNIHSASKGLPLNHAALPPTDYDRSPF
  VTSPISMTMPPHGSLQGYQTYGHFPSRAIKSEYPDPYTSSPESIMGYSYMDSYQTSSPAS
  IPHLILELLKCEPDEPQVQAKIMAYLQQEQANRSKHEKLSTFGLMCKMADQTLFSIVEWA
  RSSIFFRELKVDDQMKLLQNCWSELLILDHIYRQVVHGKEGSIFLVTGQQVDYSIIASQA
  GATLNNLMSHAQELVAKLRSLQFDQREFVCLKFLVLFSLDVKNLENFQLVEGVQEQVNAA
  LLDYTMCNYPQQTEKFGQLLLRLPEIRAISMQAEEYLYYKHLNGDVPYNNLLIEMLHAKR
  A
• Function: Nuclear receptor that acts as a key metabolic sensor by regulating the expression of genes involved in bile acid synthesis, cholesterol homeostasis and triglyceride synthesis. Together with the oxysterol receptors NR1H3/LXR-alpha and NR1H2/LXR-beta, acts as an essential transcriptional regulator of lipid metabolism. Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. Activates the transcription of CYP2C38; (Microbial infection) Plays a crucial role for hepatitis B virus gene transcription and DNA replication. Mechanistically, synergistically cooperates with HNF1A to up-regulate the activity of one of the critical cis-elements in the hepatitis B virus genome enhancer II (ENII).
• Tissue Specificity: Abundantly expressed in pancreas, less in liver, very low levels in heart and lung. Expressed in the Hep-G2 cell line. Isoform 1 and isoform 2 seem to be present in fetal and adult liver and Hep-G2 cells.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Estrogen-dependent gene expression (R-HSA-9018519)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

15 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 Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[8]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[9]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[11]
LG100268	DM41RK2	Discontinued in Phase 1	LG100268 decreases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[8]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[10]

1 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 Nuclear receptor subfamily 5 group A member 2 (NR5A2).	[6]

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] 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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [10] Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res. 2005 Dec 15;65(24):11762-70. doi: 10.1158/0008-5472.CAN-05-2792.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.