Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKYE01L)

• DOT Name: Thyroid hormone-inducible hepatic protein (THRSP)
• Synonyms: Spot 14 protein; S14; SPOT14
• Gene Name: THRSP
• Related Disease:
  Carcinoma
  Generalized resistance to thyroid hormone
  Androgen insensitivity syndrome
  Attention deficit hyperactivity disorder
  Breast carcinoma
  Hepatocellular carcinoma
  Invasive breast carcinoma
  Knee osteoarthritis
  Liposarcoma
  Neoplasm
  Non-alcoholic fatty liver disease
  Obesity
  Breast cancer
  Undifferentiated carcinoma
  Breast neoplasm
• UniProt ID: THRSP_HUMAN
• Pfam ID: PF07084
• Sequence:
  MQVLTKRYPKNCLLTVMDRYAAEVHNMEQVVMIPSLLRDVQLSGPGGQAQAEAPDLYTYF
  TMLKAICVDVDHGLLPREEWQAKVAGSEENGTAETEEVEDESASGELDLEAQFHLHFSSL
  HHILMHLTEKAQEVTRKYQEMTGQVW
• Function: Plays a role in the regulation of lipogenesis, especially in lactating mammary gland. Important for the biosynthesis of triglycerides with medium-length fatty acid chains. May modulate lipogenesis by interacting with MID1IP1 and preventing its interaction with ACACA. May function as transcriptional coactivator. May modulate the transcription factor activity of THRB.
• Tissue Specificity: Mainly expressed in tissues that synthesize triglycerides.
• Reactome Pathway: Carnitine metabolism (R-HSA-200425)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Generalized resistance to thyroid hormone	DIS4TOK0	Definitive	Biomarker	[2]
Androgen insensitivity syndrome	DISUZBBO	Strong	Altered Expression	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Invasive breast carcinoma	DISANYTW	Strong	Altered Expression	[7]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[8]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[10]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[5]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[17]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[17]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[18]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[19]
Clopidogrel	DMOL54H	Approved	Clopidogrel increases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[19]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[13]
Clemizole	DM4UAPD	Phase 1	Clemizole affects the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[19]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[22]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[23]
CITCO	DM0N634	Investigative	CITCO decreases the expression of Thyroid hormone-inducible hepatic protein (THRSP).	[19]

References

• [1] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [2] Thyroid Hormone Resistance in children.Pediatr Endocrinol Rev. 2003 Dec;1 Suppl 2:191-8; discussion 198.
• [3] Spot14/Spot14R expression may be involved in MSC adipogenic differentiation in patients with adolescent idiopathic scoliosis.Mol Med Rep. 2016 Jun;13(6):4636-42. doi: 10.3892/mmr.2016.5109. Epub 2016 Apr 12.
• [4] Overexpression of the Thyroid Hormone-Responsive (THRSP) Gene in the Striatum Leads to the Development of Inattentive-like Phenotype in Mice.Neuroscience. 2018 Oct 15;390:141-150. doi: 10.1016/j.neuroscience.2018.08.008. Epub 2018 Aug 21.
• [5] Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells.Nutr Cancer. 2009;61(1):114-22. doi: 10.1080/01635580802348666.
• [6] Combined hypermethylation and chromosome loss associated with inactivation of SSI-1/SOCS-1/JAB gene in human hepatocellular carcinomas.Cancer Lett. 2002 Dec 1;186(1):59-65. doi: 10.1016/s0304-3835(02)00244-6.
• [7] Spot 14: A marker of aggressive breast cancer and a potential therapeutic target.Endocrinology. 2006 Sep;147(9):4048-55. doi: 10.1210/en.2006-0463. Epub 2006 Jun 29.
• [8] Microarray analysis of the infrapatellar fat pad in knee osteoarthritis: relationship with joint inflammation.J Rheumatol. 2011 Sep;38(9):1966-72. doi: 10.3899/jrheum.101302. Epub 2011 Jul 15.
• [9] Modulation of tumor fatty acids, through overexpression or loss of thyroid hormone responsive protein spot 14 is associated with altered growth and metastasis.Breast Cancer Res. 2014 Dec 4;16(6):481. doi: 10.1186/s13058-014-0481-z.
• [10] MiR-451a attenuates free fatty acids-mediated hepatocyte steatosis by targeting the thyroid hormone responsive spot 14 gene.Mol Cell Endocrinol. 2018 Oct 15;474:260-271. doi: 10.1016/j.mce.2018.03.016. Epub 2018 Mar 29.
• [11] The serum level of a novel lipogenic protein Spot 14 was reduced in metabolic syndrome.PLoS One. 2019 Feb 14;14(2):e0212341. doi: 10.1371/journal.pone.0212341. eCollection 2019.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [18] Activated thyroid hormone receptor modulates dioxin-inducible aryl hydrocarbon receptor-mediated CYP1A1 induction in human hepatocytes but not in human hepatocarcinoma HepG2 cells. Toxicol Lett. 2017 Jun 5;275:77-82.
• [19] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [20] Fatty acid synthesis is a therapeutic target in human liposarcoma. Int J Oncol. 2010 May;36(5):1309-14. doi: 10.3892/ijo_00000616.
• [21] Use of transcriptomics in hazard identification and next generation risk assessment: A case study with clothianidin. Food Chem Toxicol. 2022 Aug;166:113212. doi: 10.1016/j.fct.2022.113212. Epub 2022 Jun 8.
• [22] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [23] PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. Toxicol Appl Pharmacol. 2014 Apr 1;276(1):73-81. doi: 10.1016/j.taap.2014.02.001. Epub 2014 Feb 15.