Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFYLYJ0)

• DOT Name: Type I iodothyronine deiodinase (DIO1)
• Synonyms: EC 1.21.99.4; 5DI; DIOI; Type 1 DI; Type-I 5'-deiodinase
• Gene Name: DIO1
• UniProt ID: IOD1_HUMAN
• EC Number: 1.21.99.4
• Pfam ID: PF00837
• Sequence:
  MGLPQPGLWLKRLWVLLEVAVHVVVGKVLLILFPDRVKRNILAMGEKTGMTRNPHFSHDN
  WIPTFFSTQYFWFVLKVRWQRLEDTTELGGLAPNCPVVRLSGQRCNIWEFMQGNRPLVLN
  FGSCTUPSFMFKFDQFKRLIEDFSSIADFLVIYIEEAHASDGWAFKNNMDIRNHQNLQDR
  LQAAHLLLARSPQCPVVVDTMQNQSSQLYAALPERLYIIQEGRILYKGKSGPWNYNPEEV
  RAVLEKLHS
• Function: Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into T3 (3,5,3'-triiodothyronine) and of T3 into T2 (3,3'-diiodothyronine). Plays a role in providing a source of plasma T3 by deiodination of T4 in peripheral tissues such as liver and kidney.
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway: Regulation of thyroid hormone activity (R-HSA-350864)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Liothyronine	DM6IR3P	Approved	Type I iodothyronine deiodinase (DIO1) increases the chemical synthesis of Liothyronine.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
L-thyroxine	DM83HWL	Investigative	Type I iodothyronine deiodinase (DIO1) increases the metabolism of L-thyroxine.	[17]
Triiodo-l-thyronine	DMVJD1A	Investigative	Type I iodothyronine deiodinase (DIO1) increases the metabolism of Triiodo-l-thyronine.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Type I iodothyronine deiodinase (DIO1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Type I iodothyronine deiodinase (DIO1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Type I iodothyronine deiodinase (DIO1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Type I iodothyronine deiodinase (DIO1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Type I iodothyronine deiodinase (DIO1).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Type I iodothyronine deiodinase (DIO1).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Type I iodothyronine deiodinase (DIO1).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the activity of Type I iodothyronine deiodinase (DIO1).	[7]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Type I iodothyronine deiodinase (DIO1).	[8]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Type I iodothyronine deiodinase (DIO1).	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Type I iodothyronine deiodinase (DIO1).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Type I iodothyronine deiodinase (DIO1).	[10]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Type I iodothyronine deiodinase (DIO1).	[11]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Type I iodothyronine deiodinase (DIO1).	[12]
Masoprocol	DMMVNZ0	Approved	Masoprocol decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
Oxytetracycline	DMOVH1M	Approved	Oxytetracycline decreases the activity of Type I iodothyronine deiodinase (DIO1).	[7]
Ergocalciferol	DMHO0AR	Approved	Ergocalciferol decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Type I iodothyronine deiodinase (DIO1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Type I iodothyronine deiodinase (DIO1).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the activity of Type I iodothyronine deiodinase (DIO1).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Type I iodothyronine deiodinase (DIO1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Type I iodothyronine deiodinase (DIO1).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Type I iodothyronine deiodinase (DIO1).	[16]
Morin	DM2OGZ5	Investigative	Morin decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
Fenthion	DMKEG49	Investigative	Fenthion decreases the activity of Type I iodothyronine deiodinase (DIO1).	[7]
Alpha-linolenic acid	DMY64HE	Investigative	Alpha-linolenic acid decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
BADGE	DMCK5DG	Investigative	BADGE decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]
2,3-dichloro-1,4-naphthoquinone	DMPCGSD	Investigative	2,3-dichloro-1,4-naphthoquinone decreases the activity of Type I iodothyronine deiodinase (DIO1).	[13]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] Screening the ToxCast Phase 1 Chemical Library for Inhibition of Deiodinase Type 1 Activity. Toxicol Sci. 2018 Apr 1;162(2):570-581. doi: 10.1093/toxsci/kfx279.
• [8] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [10] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [11] Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023 Mar 15;487:153461. doi: 10.1016/j.tox.2023.153461. Epub 2023 Feb 16.
• [12] 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.
• [13] Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases. Toxicol Sci. 2019 Apr 1;168(2):430-442. doi: 10.1093/toxsci/kfy302.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Regulation of type 1 iodothyronine deiodinase in health and disease. Thyroid. 2005 Aug;15(8):835-40. doi: 10.1089/thy.2005.15.835.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [17] Halogenated phenolic contaminants inhibit the in vitro activity of the thyroid-regulating deiodinases in human liver. Toxicol Sci. 2011 Dec;124(2):339-47. doi: 10.1093/toxsci/kfr117. Epub 2011 May 11.