Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFDI39D)

• DOT Name: Thyrotropin subunit beta (TSHB)
• Synonyms: Thyroid-stimulating hormone subunit beta; TSH-B; TSH-beta; Thyrotropin beta chain; Thyrotropin alfa
• Gene Name: TSHB
• Related Disease:
  Isolated thyroid-stimulating hormone deficiency
  Autoimmune thyroid disease
  Bipolar depression
  Bipolar disorder
  Congenital hypothyroidism
  Hashimoto thyroiditis
  Hepatocellular carcinoma
  Hyperthyroidism
  Pituitary gland disorder
  Turner syndrome
  Female hypogonadism
  Hypothyroidism
  Generalized resistance to thyroid hormone
  Neoplasm
• UniProt ID: TSHB_HUMAN
• PDB ID: 7T9I; 7UTZ; 7XW5
• Pfam ID: PF00007
• Sequence:
  MTALFLMSMLFGLTCGQAMSFCIPTEYTMHIERRECAYCLTINTTICAGYCMTRDINGKL
  FLPKYALSQDVCTYRDFIYRTVEIPGCPLHVAPYFSYPVALSCKCGKCNTDYSDCIHEAI
  KTNYCTKPQKSYLVGFSV
• Function: Indispensable for the control of thyroid structure and metabolism.
• 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:
  Thyroxine biosynthesis (R-HSA-209968)
  Hormone ligand-binding receptors (R-HSA-375281)
  G alpha (s) signalling events (R-HSA-418555)
  Glycoprotein hormones (R-HSA-209822)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated thyroid-stimulating hormone deficiency	DISAWYSM	Definitive	Autosomal recessive	[1]
Autoimmune thyroid disease	DISIHC6A	Strong	Altered Expression	[2]
Bipolar depression	DISA75FU	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Congenital hypothyroidism	DISL5XVU	Strong	Biomarker	[4]
Hashimoto thyroiditis	DIS77CDF	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Hyperthyroidism	DISX87ZH	Strong	Genetic Variation	[7]
Pituitary gland disorder	DIS7XB48	Strong	Altered Expression	[8]
Turner syndrome	DIS2035C	Strong	Altered Expression	[9]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[10]
Hypothyroidism	DISR0H6D	moderate	Biomarker	[11]
Generalized resistance to thyroid hormone	DIS4TOK0	Disputed	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Liothyronine	DM6IR3P	Approved	Thyrotropin subunit beta (TSHB) increases the secretion of Liothyronine.	[21]
[3H]cAMP	DMZRQU7	Investigative	Thyrotropin subunit beta (TSHB) increases the abundance of [3H]cAMP.	[22]

1 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 subunit beta (TSHB).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Thyrotropin subunit beta (TSHB).	[15]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Thyrotropin subunit beta (TSHB).	[16]
Levodopa	DMN3E57	Approved	Levodopa decreases the expression of Thyrotropin subunit beta (TSHB).	[17]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Thyrotropin subunit beta (TSHB).	[19]
Nitrate	DMVFB93	Investigative	Nitrate increases the expression of Thyrotropin subunit beta (TSHB).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Octreotide	DMHIDCJ	Approved	Octreotide decreases the secretion of Thyrotropin subunit beta (TSHB).	[18]

References

• [1] Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. EMBO J. 1989 Aug;8(8):2291-6. doi: 10.1002/j.1460-2075.1989.tb08355.x.
• [2] A newly identified TSH splice variant is involved in the pathology of Hashimoto's thyroiditis.Mol Biol Rep. 2012 Dec;39(12):10019-30. doi: 10.1007/s11033-012-1871-x. Epub 2012 Jul 3.
• [3] Thyrotrophin response to thyrotrophin-releasing hormone in unipolar and bipolar affective illness.J Affect Disord. 1981 Mar;3(1):9-16. doi: 10.1016/0165-0327(81)90014-8.
• [4] Molecular spectrum of TSH subunit gene defects in central hypothyroidism in the UK and Ireland.Clin Endocrinol (Oxf). 2017 Mar;86(3):410-418. doi: 10.1111/cen.13149. Epub 2016 Aug 4.
• [5] Functional human TSH splice variant produced by plasma cell may be involved in the immunologic injury of thyroid in the patient with Hashimoto's thyroiditis.Mol Cell Endocrinol. 2015 Oct 15;414:132-42. doi: 10.1016/j.mce.2015.06.009. Epub 2015 Jul 11.
• [6] BRCA1-mediated inflammation and growth activated & inhibited transition mechanisms between no-tumor hepatitis/cirrhotic tissues and HCC.J Cell Biochem. 2014 Apr;115(4):641-50. doi: 10.1002/jcb.24699.
• [7] Clinical manifestations of genetic defects affecting gonadotrophins and their receptors.Clin Endocrinol (Oxf). 1996 Dec;45(6):657-63. doi: 10.1046/j.1365-2265.1996.8680879.x.
• [8] Correlation of Pit-1 gene expression and Pit-1 content with proliferation and differentiation in human myeloid leukemic cells.Exp Cell Res. 1998 Nov 25;245(1):132-6. doi: 10.1006/excr.1998.4232.
• [9] Autoimmune hypothyroidism and hyperthyroidism in patients with Turner's syndrome.Eur J Endocrinol. 1996 May;134(5):568-75. doi: 10.1530/eje.0.1340568.
• [10] Epistasis between polymorphisms in TSHB and ADAMTS16 is associated with premature ovarian failure.Menopause. 2014 Aug;21(8):890-5. doi: 10.1097/GME.0000000000000172.
• [11] Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence.Cell Physiol Biochem. 2018;51(1):142-153. doi: 10.1159/000495170. Epub 2018 Nov 16.
• [12] Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance.J Clin Endocrinol Metab. 1994 May;78(5):1034-9. doi: 10.1210/jcem.78.5.8175956.
• [13] A Patient With a Thyrotropin-Secreting Microadenoma and Resistance to Thyroid Hormone (P453T).J Clin Endocrinol Metab. 2015 Jul;100(7):2511-4. doi: 10.1210/jc.2014-3994. Epub 2015 Apr 13.
• [14] 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.
• [15] Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients--a pilot study. Anticancer Res. 2007 Jul-Aug;27(4A):1883-6.
• [16] Effect of 1 alpha-hydroxyvitamin D3 on serum levels of thyroid hormones in hyperthyroid patients with untreated Graves' disease. Metabolism. 1997 Oct;46(10):1184-8. doi: 10.1016/s0026-0495(97)90214-6.
• [17] Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study versus placebo. Clin Neuropharmacol. 1996 Feb;19(1):72-80. doi: 10.1097/00002826-199619010-00006.
• [18] Long-term efficacy and tolerability of octreotide treatment in acromegaly. Metabolism. 1992 Sep;41(9 Suppl 2):44-50. doi: 10.1016/0026-0495(92)90030-e.
• [19] Post-myocardial infarction mortality in patients with ventricular premature depolarizations. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Pilot Study. Circulation. 1991 Aug;84(2):550-7. doi: 10.1161/01.cir.84.2.550.
• [20] Goitrogenic anions, thyroid-stimulating hormone, and thyroid hormone in infants. Environ Health Perspect. 2010 Sep;118(9):1332-7. doi: 10.1289/ehp.0901736. Epub 2010 Apr 27.
• [21] Amiodarone stimulates interleukin-6 production in cultured human thyrocytes, exerting cytotoxic effects on thyroid follicles in suspension culture. Thyroid. 2001 Feb;11(2):101-9. doi: 10.1089/105072501300042703.
• [22] Enhanced photodynamic effect of cobalt(III) dipyridophenazine complex on thyrotropin receptor expressing HEK293 cells. Metallomics. 2010 Nov;2(11):754-65. doi: 10.1039/c0mt00028k. Epub 2010 Oct 21.