Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0BC8LB)

• DOT Name: Thyrotropin receptor (TSHR)
• Synonyms: Thyroid-stimulating hormone receptor; TSH-R
• Gene Name: TSHR
• Related Disease:
  Familial gestational hyperthyroidism
  Hypothyroidism due to TSH receptor mutations
  Familial hyperthyroidism due to mutations in TSH receptor
  Athyreosis
  Thyroid hypoplasia
• UniProt ID: TSHR_HUMAN
• PDB ID: 2XWT; 3G04; 7T9M; 7XW5; 7XW6; 7XW7
• Pfam ID: PF00001 ; PF13306
• Sequence:
  MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLI
  ETHLRTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPD
  ALKELPLLKFLGIFNTGLKMFPDLTKVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETL
  TLKLYNNGFTSVQGYAFNGTKLDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTA
  LPSKGLEHLKELIARNTWTLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLM
  CNESSMQSLRQRKSVNALNSPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQE
  DEIIGFGQELKNPQEETLQAFDSHYDYTICGDSEDMVCTPKSDEFNPCEDIMGYKFLRIV
  VWFVSLLALLGNVFVLLILLTSHYKLNVPRFLMCNLAFADFCMGMYLLLIASVDLYTHSE
  YYNHAIDWQTGPGCNTAGFFTVFASELSVYTLTVITLERWYAITFAMRLDRKIRLRHACA
  IMVGGWVCCFLLALLPLVGISSYAKVSICLPMDTETPLALAYIVFVLTLNIVAFVIVCCC
  YVKIYITVRNPQYNPGDKDTKIAKRMAVLIFTDFICMAPISFYALSAILNKPLITVSNSK
  ILLVLFYPLNSCANPFLYAIFTKAFQRDVFILLSKFGICKRQAQAYRGQRVPPKNSTDIQ
  VQKVTHDMRQGLHNMEDVYELIENSHLTPKKQGQISEEYMQTVL
• Function: Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin. Also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Plays a central role in controlling thyroid cell metabolism.
• Tissue Specificity: Expressed in thyroide cells (at protein level) . Expressed in the thyroid .
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Thyroid hormone synthesis (hsa04918)
  Regulation of lipolysis in adipocytes (hsa04923)
  Autoimmune thyroid disease (hsa05320)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Hormone ligand-binding receptors (R-HSA-375281)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial gestational hyperthyroidism	DIS0OC59	Definitive	Autosomal dominant	[1]
Hypothyroidism due to TSH receptor mutations	DIS507FJ	Definitive	Autosomal recessive	[2]
Familial hyperthyroidism due to mutations in TSH receptor	DIS8F8F5	Strong	Autosomal dominant	[3]
Athyreosis	DISBHHCU	Supportive	Autosomal dominant	[4]
Thyroid hypoplasia	DISJG17B	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	Thyrotropin receptor (TSHR) increases the abundance of [3H]cAMP.	[16]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Thyrotropin receptor (TSHR).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Thyrotropin receptor (TSHR).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Thyrotropin receptor (TSHR).	[15]

10 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 Thyrotropin receptor (TSHR).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thyrotropin receptor (TSHR).	[8]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Thyrotropin receptor (TSHR).	[9]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Thyrotropin receptor (TSHR).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Thyrotropin receptor (TSHR).	[7]
Methimazole	DM25FL8	Approved	Methimazole decreases the expression of Thyrotropin receptor (TSHR).	[11]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Thyrotropin receptor (TSHR).	[12]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the expression of Thyrotropin receptor (TSHR).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thyrotropin receptor (TSHR).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Thyrotropin receptor (TSHR).	[7]

References

• [1] Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med. 1998 Dec 17;339(25):1823-6. doi: 10.1056/NEJM199812173392505.
• [2] Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol Metab. 1997 Oct;82(10):3471-80. doi: 10.1210/jcem.82.10.4286.
• [3] Mutations in the mouse TSH receptor equivalent to human constitutively activating TSH receptor mutations also cause constitutive activity. Horm Metab Res. 2001 May;33(5):263-9. doi: 10.1055/s-2001-15119.
• [4] Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor. Clin Endocrinol (Oxf). 2004 Feb;60(2):220-7. doi: 10.1111/j.1365-2265.2004.01967.x.
• [5] Functional characterization of the novel sequence variant p.S304R in the hinge region of TSHR in a congenital hypothyroidism patients and analogy with other formerly known mutations of this gene portion. J Pediatr Endocrinol Metab. 2015 Jul;28(7-8):777-84. doi: 10.1515/jpem-2014-0194.
• [6] 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.
• [7] The comparative effects of gene modulators on thyroid-specific genes and radioiodine uptake. Cancer Biother Radiopharm. 2007 Jun;22(3):443-9. doi: 10.1089/cbr.2006.319.A.
• [8] Synergy between HDAC and PARP Inhibitors on Proliferation of a Human Anaplastic Thyroid Cancer-Derived Cell Line. Int J Endocrinol. 2015;2015:978371. doi: 10.1155/2015/978371. Epub 2015 Jan 29.
• [9] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [10] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [11] Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):81-8. doi: 10.1016/j.taap.2012.01.029. Epub 2012 Feb 8.
• [12] Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma. J Clin Endocrinol Metab. 2005 Oct;90(10):5663-71. doi: 10.1210/jc.2005-0367. Epub 2005 Jul 19.
• [13] 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.
• [14] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [15] 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.
• [16] A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J Clin Endocrinol Metab. 2011 Feb;96(2):548-54. doi: 10.1210/jc.2010-1935. Epub 2010 Dec 1.