Details of the Drug Combination

General Information of Drug Combination (ID: DCJDNP5)

• Drug Combination Name: Methimazole + Propylthiouracil
• Indication: Microbiota; Status: Phase 1 [1]
• Component Drugs:
  Methimazole (DM25FL8): Small molecular drug
  Propylthiouracil (DM6D7N8): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Methimazole

Disease Entry	ICD 11	Status	REF
Hyperthyroidism	5A02	Approved	[2]

Methimazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Thyroid peroxidase (TPO)	TT52XDZ	PERT_HUMAN	Inhibitor	[6]

Methimazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Dimethylaniline oxidase 2 (FMO2)	DEIASEZ	FMO2_HUMAN	Metabolism	[7]

Methimazole Interacts with 43 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[8]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Increases Activity	[9]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[5]
Trans-Golgi network integral membrane protein 2 (TGOLN2)	OTM647IV	TGON2_HUMAN	Increases Expression	[5]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Increases Expression	[10]
Haptoglobin (HP)	OTGUGAF9	HPT_HUMAN	Increases Expression	[10]
Thyrotropin subunit beta (TSHB)	OTFDI39D	TSHB_HUMAN	Increases Expression	[11]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Expression	[12]
Alpha-fetoprotein (AFP)	OT9GG3ZI	FETA_HUMAN	Increases Expression	[12]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Decreases Expression	[12]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Decreases Expression	[12]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[10]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Decreases Activity	[13]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[12]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Microsomal glutathione S-transferase 1 (MGST1)	OTGN1KVZ	MGST1_HUMAN	Increases Expression	[10]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[12]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[5]
Thyrotropin receptor (TSHR)	OT0BC8LB	TSHR_HUMAN	Decreases Expression	[14]
Galectin-3 (LGALS3)	OTYQT0ZI	LEG3_HUMAN	Increases Expression	[10]
Integrin beta-5 (ITGB5)	OT21MF51	ITB5_HUMAN	Increases Expression	[5]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[12]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[12]
RAC-beta serine/threonine-protein kinase (AKT2)	OTBB632K	AKT2_HUMAN	Decreases Expression	[12]
Hepatocyte nuclear factor 4-alpha (HNF4A)	OTY1TOAB	HNF4A_HUMAN	Increases Expression	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[12]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[10]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Decreases Expression	[12]
Type I iodothyronine deiodinase (DIO1)	OTFYLYJ0	IOD1_HUMAN	Increases Expression	[14]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Decreases Expression	[10]
Low-density lipoprotein receptor-related protein 2 (LRP2)	OTZ6W681	LRP2_HUMAN	Increases Expression	[14]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[5]
DNA-binding protein inhibitor ID-3 (ID3)	OTUULW5Z	ID3_HUMAN	Increases Expression	[5]
Krueppel-like factor 9 (KLF9)	OTBFEJRQ	KLF9_HUMAN	Increases Expression	[5]
Consortin (CNST)	OTOUCB98	CNST_HUMAN	Increases Expression	[5]
Sodium/iodide cotransporter (SLC5A5)	OTU7E9G7	SC5A5_HUMAN	Increases Expression	[14]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[15]
PTB domain-containing engulfment adapter protein 1 (GULP1)	OT1WMVDH	GULP1_HUMAN	Increases Expression	[5]
Flavin-containing monooxygenase 3 (FMO3)	OT1G2EV3	FMO3_HUMAN	Increases Metabolism	[16]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Metabolism	[17]
Flavin-containing monooxygenase 1 (FMO1)	OTTHSQKP	FMO1_HUMAN	Increases Oxidation	[18]
Flavin-containing monooxygenase 2 (FMO2)	OTUJUL9S	FMO2_HUMAN	Decreases Oxidation	[19]

Indication(s) of Propylthiouracil

Disease Entry	ICD 11	Status	REF
Hyperthyroidism	5A02	Approved	[3]
Thyroid crisis	N.A.	Approved	[4]

Propylthiouracil Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Iodothyronine deiodinase type I (DIO1)	TTU3X26	IOD1_HUMAN	Inhibitor	[20]
Thyroid peroxidase (TPO)	TT52XDZ	PERT_HUMAN	Inhibitor	[21]

Propylthiouracil Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Taste receptor type 2 member 38 (TAS2R38)	OTX5MM36	T2R38_HUMAN	Increases Activity	[22]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[5]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[15]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Decreases Expression	[14]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Decreases Activity	[23]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Decreases Expression	[14]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Decreases Expression	[14]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[5]
Integrin beta-5 (ITGB5)	OT21MF51	ITB5_HUMAN	Decreases Expression	[5]
Low-density lipoprotein receptor-related protein 2 (LRP2)	OTZ6W681	LRP2_HUMAN	Decreases Expression	[14]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[24]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[5]
DNA-binding protein inhibitor ID-3 (ID3)	OTUULW5Z	ID3_HUMAN	Increases Expression	[5]
Krueppel-like factor 9 (KLF9)	OTBFEJRQ	KLF9_HUMAN	Increases Expression	[5]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[15]
Carbonic anhydrase 6 (CA6)	OTIX56CJ	CAH6_HUMAN	Affects Response To Substance	[25]
Mitochondrial substrate carrier family protein ancA (ancA?)	OTTU3FKC	ADT_DICDI	Increases ADR	[26]
Basic salivary proline-rich protein 1 (PRB1)	OTV0SYMD	PRP1_HUMAN	Affects Response To Substance	[25]

References

• [1] ClinicalTrials.gov (NCT03433352) Intestinal Microbiota and Treatment of GD
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6649).
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6650).
• [4] Propylthiouracil FDA Label
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• [12] Low-expressional IGF1 mediated methimazole-induced liver developmental toxicity in fetal mice. Toxicology. 2018 Sep 1;408:70-79. doi: 10.1016/j.tox.2018.07.004. Epub 2018 Jul 7.
• [13] 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.
• [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] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [16] Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. J Pharmacol Exp Ther. 2007 Jan;320(1):266-73. doi: 10.1124/jpet.106.112268. Epub 2006 Oct 18.
• [17] Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity. Chem Res Toxicol. 2021 Dec 20;34(12):2534-2539. doi: 10.1021/acs.chemrestox.1c00300. Epub 2021 Nov 17.
• [18] Evaluation of xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Toxicol Sci. 2004 Apr;78(2):196-203.
• [19] Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenet Genomics. 2005 Apr;15(4):245-56. doi: 10.1097/01213011-200504000-00008.
• [20] Type 1 iodothyronine deiodinase is the major source of circulating T3 in hyperthyroidism: implications for therapy. Nat Clin Pract Endocrinol Metab. 2007 Nov;3(11):740-1.
• [21] Bioinorganic chemistry in thyroid gland: effect of antithyroid drugs on peroxidase-catalyzed oxidation and iodination reactions. Bioinorg Chem Appl. 2006:23214.
• [22] Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 2011;6(5):e20123.
• [23] Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiouracil (PTU) and anti-MPO antibodies from patients with PTU-induced vasculitis. Clin Immunol. 2007 Feb;122(2):187-93. doi: 10.1016/j.clim.2006.09.011. Epub 2006 Oct 27.
• [24] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [25] Responsiveness to 6-n-propylthiouracil (PROP) is associated with salivary levels of two specific basic proline-rich proteins in humans. PLoS One. 2012;7(2):e30962. doi: 10.1371/journal.pone.0030962. Epub 2012 Feb 1.
• [26] 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.