Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKRLVD7)

• DOT Name: Thyroid hormone receptor alpha (THRA)
• Synonyms: Nuclear receptor subfamily 1 group A member 1; V-erbA-related protein 7; EAR-7; c-erbA-1; c-erbA-alpha
• Gene Name: THRA
• Related Disease: Congenital nongoitrous hypothryoidism 6
• UniProt ID: THA_HUMAN
• PDB ID: 1NAV; 2H77; 2H79; 3HZF; 3ILZ; 3JZB; 4LNW; 4LNX; 7QDT
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MEQKPSKVECGSDPEENSARSPDGKRKRKNGQCSLKTSMSGYIPSYLDKDEQCVVCGDKA
  TGYHYRCITCEGCKGFFRRTIQKNLHPTYSCKYDSCCVIDKITRNQCQLCRFKKCIAVGM
  AMDLVLDDSKRVAKRKLIEQNRERRRKEEMIRSLQQRPEPTPEEWDLIHIATEAHRSTNA
  QGSHWKQRRKFLPDDIGQSPIVSMPDGDKVDLEAFSEFTKIITPAITRVVDFAKKLPMFS
  ELPCEDQIILLKGCCMEIMSLRAAVRYDPESDTLTLSGEMAVKREQLKNGGLGVVSDAIF
  ELGKSLSAFNLDDTEVALLQAVLLMSTDRSGLLCVDKIEKSQEAYLLAFEHYVNHRKHNI
  PHFWPKLLMKEREVQSSILYKGAAAEGRPGGSLGVHPEGQQLLGMHVVQGPQVRQLEQQL
  GEAGSLQGPVLQHQSPKSPQQRLLELLHRSGILHARAVCGEDDSSEADSPSSSEEEPEVC
  EDLAGNAASP
• Function: [Isoform Alpha-1]: Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine; [Isoform Alpha-2]: Does not bind thyroid hormone and functions as a weak dominant negative inhibitor of thyroid hormone action.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway:
  (Name not found)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital nongoitrous hypothryoidism 6	DISAOZYW	Definitive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Thyroid hormone receptor alpha (THRA).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thyroid hormone receptor alpha (THRA).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Thyroid hormone receptor alpha (THRA).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thyroid hormone receptor alpha (THRA).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Thyroid hormone receptor alpha (THRA).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thyroid hormone receptor alpha (THRA).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Thyroid hormone receptor alpha (THRA).	[8]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Thyroid hormone receptor alpha (THRA).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Thyroid hormone receptor alpha (THRA).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Thyroid hormone receptor alpha (THRA).	[15]
L-thyroxine	DM83HWL	Investigative	L-thyroxine increases the expression of Thyroid hormone receptor alpha (THRA).	[16]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Genistein	DM0JETC	Phase 2/3	Genistein affects the binding of Thyroid hormone receptor alpha (THRA).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone affects the binding of Thyroid hormone receptor alpha (THRA).	[11]
Daidzein	DMRFTJX	Investigative	Daidzein affects the binding of Thyroid hormone receptor alpha (THRA).	[10]

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 decreases the methylation of Thyroid hormone receptor alpha (THRA).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Thyroid hormone receptor alpha (THRA).	[14]

References

• [1] A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012 Jan 19;366(3):243-9. doi: 10.1056/NEJMoa1110296. Epub 2011 Dec 14.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Changes in gene expression and assessment of DNA methylation in primary human hepatocytes and HepG2 cells exposed to the environmental contaminants-Hexabromocyclododecane and 17-beta oestradiol. Toxicology. 2009 Feb 27;256(3):143-51. doi: 10.1016/j.tox.2008.10.017. Epub 2008 Nov 5.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [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] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [10] A Possible Novel Mechanism of Action of Genistein and Daidzein for Activating Thyroid Hormone Receptor-Mediated Transcription. Toxicol Sci. 2018 Aug 1;164(2):417-427. doi: 10.1093/toxsci/kfy097.
• [11] Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone. J Med Chem. 2002 Jan 31;45(3):623-30. doi: 10.1021/jm001126+.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Establishment of transactivation assay systems using fish, amphibian, reptilian and human thyroid hormone receptors. J Appl Toxicol. 2013 Sep;33(9):991-1000. doi: 10.1002/jat.2825. Epub 2012 Oct 30.