Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH8A44K)

• DOT Name: Progonadoliberin-1 (GNRH1)
• Synonyms: Progonadoliberin I
• Gene Name: GNRH1
• Related Disease:
  Hypogonadotropic hypogonadism 12 with or without anosmia
  Hypogonadotropic hypogonadism
• UniProt ID: GON1_HUMAN
• PDB ID: 4D5M
• Pfam ID: PF00446
• Sequence:
  MKPIQKLLAGLILLTWCVEGCSSQHWSYGLRPGGKRDAENLIDSFQEIVKEVGQLAETQR
  FECTTHQPRSPLRDLKGALESLIEEETGQKKI
• Function: Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  GnRH sig.ling pathway (hsa04912)
  GnRH secretion (hsa04929)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Hormone ligand-binding receptors (R-HSA-375281)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 12 with or without anosmia	DISVDHZQ	Strong	Autosomal recessive	[1]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Progonadoliberin-1 (GNRH1) decreases the abundance of Progesterone.	[11]

9 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 Progonadoliberin-1 (GNRH1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Progonadoliberin-1 (GNRH1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Progonadoliberin-1 (GNRH1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Progonadoliberin-1 (GNRH1).	[6]
Propofol	DMB4OLE	Approved	Propofol increases the expression of Progonadoliberin-1 (GNRH1).	[7]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Progonadoliberin-1 (GNRH1).	[7]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the activity of Progonadoliberin-1 (GNRH1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Progonadoliberin-1 (GNRH1).	[9]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Progonadoliberin-1 (GNRH1).	[10]

References

• [1] Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. 2009 Jun 25;360(26):2742-8. doi: 10.1056/NEJMoa0900136. Epub 2009 Jun 17.
• [2] Genetics defects in GNRH1: a paradigm of hypothalamic congenital gonadotropin deficiency. Brain Res. 2010 Dec 10;1364:3-9. doi: 10.1016/j.brainres.2010.09.084. Epub 2010 Sep 29.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [8] A single dose of the potent gonadotropin-releasing hormone antagonist acyline suppresses gonadotropins and testosterone for 2 weeks in healthy young men. J Clin Endocrinol Metab. 2004 Dec;89(12):5959-65. doi: 10.1210/jc.2003-032123.
• [9] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [10] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [11] Hecate-CGbeta conjugate and gonadotropin suppression shows two distinct mechanisms of action in the treatment of adrenocortical tumors in transgenic mice expressing Simian Virus 40 T antigen under inhibin-alpha promoter. Endocr Relat Cancer. 2009 Jun;16(2):549-64. doi: 10.1677/ERC-08-0232. Epub 2009 Mar 4.