Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJJLL20)

• DOT Name: Thyroid peroxidase (TPO)
• Synonyms: TPO; EC 1.11.1.8
• Gene Name: TPO
• Related Disease:
  Thyroid dyshormonogenesis 2A
  Familial thyroid dyshormonogenesis
• UniProt ID: PERT_HUMAN
• EC Number: 1.11.1.8
• Pfam ID: PF03098 ; PF07645 ; PF00084
• Sequence:
  MRALAVLSVTLVMACTEAFFPFISRGKELLWGKPEESRVSSVLEESKRLVDTAMYATMQR
  NLKKRGILSPAQLLSFSKLPEPTSGVIARAAEIMETSIQAMKRKVNLKTQQSQHPTDALS
  EDLLSIIANMSGCLPYMLPPKCPNTCLANKYRPITGACNNRDHPRWGASNTALARWLPPV
  YEDGFSQPRGWNPGFLYNGFPLPPVREVTRHVIQVSNEVVTDDDRYSDLLMAWGQYIDHD
  IAFTPQSTSKAAFGGGADCQMTCENQNPCFPIQLPEEARPAAGTACLPFYRSSAACGTGD
  QGALFGNLSTANPRQQMNGLTSFLDASTVYGSSPALERQLRNWTSAEGLLRVHARLRDSG
  RAYLPFVPPRAPAACAPEPGIPGETRGPCFLAGDGRASEVPSLTALHTLWLREHNRLAAA
  LKALNAHWSADAVYQEARKVVGALHQIITLRDYIPRILGPEAFQQYVGPYEGYDSTANPT
  VSNVFSTAAFRFGHATIHPLVRRLDASFQEHPDLPGLWLHQAFFSPWTLLRGGGLDPLIR
  GLLARPAKLQVQDQLMNEELTERLFVLSNSSTLDLASINLQRGRDHGLPGYNEWREFCGL
  PRLETPADLSTAIASRSVADKILDLYKHPDNIDVWLGGLAENFLPRARTGPLFACLIGKQ
  MKALRDGDWFWWENSHVFTDAQRRELEKHSLSRVICDNTGLTRVPMDAFQVGKFPEDFES
  CDSITGMNLEAWRETFPQDDKCGFPESVENGDFVHCEESGRRVLVYSCRHGYELQGREQL
  TCTQEGWDFQPPLCKDVNECADGAHPPCHASARCRNTKGGFQCLCADPYELGDDGRTCVD
  SGRLPRVTWISMSLAALLIGGFAGLTSTVICRWTRTGTKSTLPISETGGGTPELRCGKHQ
  AVGTSPQRAAAQDSEQESAGMEGRDTHRLPRAL
• Function: Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
  Thyroid hormone synthesis (hsa04918)
  Autoimmune thyroid disease (hsa05320)
• Reactome Pathway: Thyroxine biosynthesis (R-HSA-209968)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid dyshormonogenesis 2A	DIS74XBI	Strong	Autosomal recessive	[1]
Familial thyroid dyshormonogenesis	DISALTXN	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Leuprolide	DM5XPIJ	Approved	Thyroid peroxidase (TPO) increases the Thyroid disorder ADR of Leuprolide.	[19]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
IODIDE	DM3FZ6P	Investigative	Thyroid peroxidase (TPO) increases the oxidation of IODIDE.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Thyroid peroxidase (TPO).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Thyroid peroxidase (TPO).	[4]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Thyroid peroxidase (TPO).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Thyroid peroxidase (TPO).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Thyroid peroxidase (TPO).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thyroid peroxidase (TPO).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Thyroid peroxidase (TPO).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the activity of Thyroid peroxidase (TPO).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thyroid peroxidase (TPO).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Thyroid peroxidase (TPO).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Thyroid peroxidase (TPO).	[5]
Glutathione	DMAHMT9	Approved	Glutathione decreases the activity of Thyroid peroxidase (TPO).	[8]
Methimazole	DM25FL8	Approved	Methimazole decreases the activity of Thyroid peroxidase (TPO).	[12]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Thyroid peroxidase (TPO).	[13]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the expression of Thyroid peroxidase (TPO).	[13]
Propylthiouracil	DM6D7N8	Approved	Propylthiouracil decreases the expression of Thyroid peroxidase (TPO).	[14]
Oxymetholone	DMFXUT8	Approved	Oxymetholone increases the expression of Thyroid peroxidase (TPO).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Thyroid peroxidase (TPO).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the activity of Thyroid peroxidase (TPO).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Thyroid peroxidase (TPO).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Thyroid peroxidase (TPO).	[17]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the activity of Thyroid peroxidase (TPO).	[18]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the activity of Thyroid peroxidase (TPO).	[12]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the activity of Thyroid peroxidase (TPO).	[18]

References

• [1] Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab. 2000 Oct;85(10):3708-12. doi: 10.1210/jcem.85.10.6878.
• [2] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] 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.
• [7] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [8] Arsenic trioxide and reduced glutathione act synergistically to augment inhibition of thyroid peroxidase activity in vitro. Biol Trace Elem Res. 2015 May;165(1):110-7. doi: 10.1007/s12011-015-0230-x. Epub 2015 Jan 17.
• [9] Robust Thyroid Gene Expression and Radioiodine Uptake Induced by Simultaneous Suppression of BRAF V600E and Histone Deacetylase in Thyroid Cancer Cells. J Clin Endocrinol Metab. 2016 Mar;101(3):962-71. doi: 10.1210/jc.2015-3433. Epub 2016 Jan 11.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] 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.
• [12] Identification of classifiers for increase or decrease of thyroid peroxidase activity in the FTC-238/hTPO recombinant cell line. Environ Sci Technol. 2011 Sep 15;45(18):7906-14. doi: 10.1021/es200475k. Epub 2011 Aug 24.
• [13] 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.
• [14] 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.
• [15] Direct and indirect effects of androgens on survival of hematopoietic progenitor cells in vitro. J Korean Med Sci. 2005 Jun;20(3):409-16. doi: 10.3346/jkms.2005.20.3.409.
• [16] Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles. Thyroid. 2007 Dec;17(12):1189-200. doi: 10.1089/thy.2007.0215.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] A rapid assay of human thyroid peroxidase activity. Toxicol In Vitro. 2020 Feb;62:104662. doi: 10.1016/j.tiv.2019.104662. Epub 2019 Oct 16.
• [19] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.