Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY1TOAB)

• DOT Name: Hepatocyte nuclear factor 4-alpha (HNF4A)
• Synonyms: HNF-4-alpha; Nuclear receptor subfamily 2 group A member 1; Transcription factor 14; TCF-14; Transcription factor HNF-4
• Gene Name: HNF4A
• Related Disease:
  Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
  Maturity-onset diabetes of the young type 1
  Monogenic diabetes
  Obsolete diabetes mellitus, noninsulin-dependent
  Hyperinsulinism due to HNF4A deficiency
  Maturity-onset diabetes of the young
• UniProt ID: HNF4A_HUMAN
• PDB ID: 1PZL; 3CBB; 3FS1; 4B7W; 4IQR; 6CHT
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGNDTSPSEGTNLNAPNSLGVSALC
  AICGDRATGKHYGASSCDGCKGFFRRSVRKNHMYSCRFSRQCVVDKDKRNQCRYCRLKKC
  FRAGMKKEAVQNERDRISTRRSSYEDSSLPSINALLQAEVLSRQITSPVSGINGDIRAKK
  IASIADVCESMKEQLLVLVEWAKYIPAFCELPLDDQVALLRAHAGEHLLLGATKRSMVFK
  DVLLLGNDYIVPRHCPELAEMSRVSIRILDELVLPFQELQIDDNEYAYLKAIIFFDPDAK
  GLSDPGKIKRLRSQVQVSLEDYINDRQYDSRGRFGELLLLLPTLQSITWQMIEQIQFIKL
  FGMAKIDNLLQEMLLGGSPSDAPHAHHPLHPHLMQEHMGTNVIVANTMPTHLSNGQMCEW
  PRPRGQAATPETPQPSPPGGSGSEPYKLLPGAVATIVKPLSAIPQPTITKQEVI
• Function: Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes. Activates the transcription of CYP2C38. Represses the CLOCK-BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells.
• KEGG Pathway:
  AMPK sig.ling pathway (hsa04152)
  Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	DIS4NNOZ	Definitive	Autosomal dominant	[1]
Maturity-onset diabetes of the young type 1	DISADKR0	Definitive	Autosomal dominant	[2]
Monogenic diabetes	DISEB8Q0	Definitive	Autosomal dominant	[3]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Strong	Autosomal dominant	[4]
Hyperinsulinism due to HNF4A deficiency	DISF4UK5	Supportive	Autosomal dominant	[5]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[6]

28 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 Hepatocyte nuclear factor 4-alpha (HNF4A).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the activity of Hepatocyte nuclear factor 4-alpha (HNF4A).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[16]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[17]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[18]
Estriol	DMOEM2I	Approved	Estriol decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[11]
Fructose	DM43AN2	Approved	Fructose decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[19]
SR141716A	DMCO5JZ	Approved	SR141716A decreases the activity of Hepatocyte nuclear factor 4-alpha (HNF4A).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[22]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[23]
Baicalin	DMY1TLZ	Terminated	Baicalin decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[7]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[19]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[25]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[26]
U0126	DM31OGF	Investigative	U0126 increases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[27]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One increases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[28]
propylpyrazoletriol	DMTCP8K	Investigative	propylpyrazoletriol decreases the expression of Hepatocyte nuclear factor 4-alpha (HNF4A).	[11]

References

• [1] The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a cell phenotype. J Med Genet. 2014 Mar;51(3):165-9. doi: 10.1136/jmedgenet-2013-102066. Epub 2013 Nov 27.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Congenital hyperinsulinism due to mutations in HNF4A and HADH. Rev Endocr Metab Disord. 2010 Sep;11(3):185-91. doi: 10.1007/s11154-010-9148-y.
• [6] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [7] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [8] 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.
• [9] Repression of hepatocyte nuclear factor 4 alpha by AP-1 underlies dyslipidemia associated with retinoic acid. J Lipid Res. 2019 Apr;60(4):794-804. doi: 10.1194/jlr.M088880. Epub 2019 Feb 1.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] The effect of estrogen compounds on human embryoid bodies. Reprod Sci. 2013 Jun;20(6):661-9. doi: 10.1177/1933719112462630. Epub 2012 Nov 26.
• [12] Chrysin ameliorates hepatic steatosis induced by a diet deficient in methionine and choline by inducing the secretion of hepatocyte nuclear factor 4-dependent very low-density lipoprotein. J Biochem Mol Toxicol. 2020 Jul;34(7):e22497. doi: 10.1002/jbt.22497. Epub 2020 Mar 27.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [15] Dexamethasone-mediated up-regulation of human CYP2A6 involves the glucocorticoid receptor and increased binding of hepatic nuclear factor 4 alpha to the proximal promoter. Mol Pharmacol. 2008 Feb;73(2):451-60.
• [16] Self-assembled 3D spheroids and hollow-fibre bioreactors improve MSC-derived hepatocyte-like cell maturation in vitro. Arch Toxicol. 2017 Apr;91(4):1815-1832.
• [17] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [18] Low-expressional IGF1 mediated methimazole-induced liver developmental toxicity in fetal mice. Toxicology. 2018 Sep 1;408:70-79. doi: 10.1016/j.tox.2018.07.004. Epub 2018 Jul 7.
• [19] Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest. 2007 Dec;117(12):3979-87. doi: 10.1172/JCI32249.
• [20] Rimonabant suppresses RNA transcription of hepatitis B virus by inhibiting hepatocyte nuclear factor 4. Microbiol Immunol. 2020 May;64(5):345-355. doi: 10.1111/1348-0421.12777. Epub 2020 Feb 25.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Suppression of the pregnane X receptor during endoplasmic reticulum stress is achieved by down-regulating hepatocyte nuclear factor-4 and up-regulating liver-enriched inhibitory protein. Toxicol Sci. 2015 Apr;144(2):382-92. doi: 10.1093/toxsci/kfv008. Epub 2015 Jan 22.
• [23] Metabolism and Toxicity of Emodin: Genome-Wide Association Studies Reveal Hepatocyte Nuclear Factor 4 Regulates UGT2B7 and Emodin Glucuronidation. Chem Res Toxicol. 2020 Jul 20;33(7):1798-1808. doi: 10.1021/acs.chemrestox.0c00047. Epub 2020 Jul 7.
• [24] Baicalin down-regulating hepatitis B virus transcription depends on the liver-specific HNF4-HNF1 axis. Toxicol Appl Pharmacol. 2020 Sep 15;403:115131. doi: 10.1016/j.taap.2020.115131. Epub 2020 Jul 17.
• [25] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [26] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [27] U0126, a mitogen-activated protein kinase kinase 1 and 2 (MEK1 and 2) inhibitor, selectively up-regulates main isoforms of CYP3A subfamily via a pregnane X receptor (PXR) in HepG2 cells. Arch Toxicol. 2014 Dec;88(12):2243-59.
• [28] Role of the nuclear receptors HNF4 alpha, PPAR alpha, and LXRs in the TNF alpha-mediated inhibition of human apolipoprotein A-I gene expression in HepG2 cells. Biochemistry. 2009 Dec 22;48(50):11950-60. doi: 10.1021/bi9015742.