Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2MOC4T)

• DOT Name: Corticoliberin (CRH)
• Synonyms: Corticotropin-releasing factor; CRF; Corticotropin-releasing hormone
• Gene Name: CRH
• Related Disease:
  Autosomal dominant nocturnal frontal lobe epilepsy
  Frontal lobe epilepsy
  Epilepsy
• UniProt ID: CRF_HUMAN
• PDB ID: 1GO9; 1GOE; 3EHT; 3EHU; 6P9X
• Pfam ID: PF00473
• Sequence:
  MRLPLLVSAGVLLVALLPCPPCRALLSRGPVPGARQAPQHPQPLDFFQPPPQSEQPQQPQ
  ARPVLLRMGEEYFLRLGNLNKSPAAPLSPASSLLAGGSGSRPSPEQATANFFRVLLQQLL
  LPRRSLDSPAALAERGARNALGGHQEAPERERRSEEPPISLDLTFHLLREVLEMARAEQL
  AQQAHSNRKLMEIIGK
• Function: Hormone regulating the release of corticotropin from pituitary gland. Induces NLRP6 in intestinal epithelial cells, hence may influence gut microbiota profile.
• Tissue Specificity: Produced by the hypothalamus and placenta.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Long-term depression (hsa04730)
  Cushing syndrome (hsa04934)
  Alcoholism (hsa05034)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  MECP2 regulates transcription of neuronal ligands (R-HSA-9022702)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nocturnal frontal lobe epilepsy	DISE3C4O	Supportive	Autosomal dominant	[1]
Frontal lobe epilepsy	DISHN8AO	Limited	Autosomal dominant	[2]
Epilepsy	DISBB28L	Refuted	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Corticoliberin (CRH) decreases the abundance of Progesterone.	[16]
Hydrocortisone	DMGEMB7	Approved	Corticoliberin (CRH) increases the abundance of Hydrocortisone.	[17]

15 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 Corticoliberin (CRH).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Corticoliberin (CRH).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Corticoliberin (CRH).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Corticoliberin (CRH).	[7]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Corticoliberin (CRH).	[8]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Corticoliberin (CRH).	[9]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Corticoliberin (CRH).	[8]
Thioridazine	DM35M8J	Approved	Thioridazine decreases the expression of Corticoliberin (CRH).	[8]
Risperidone	DMN6DXL	Approved	Risperidone decreases the expression of Corticoliberin (CRH).	[8]
Terbutaline	DMD4381	Approved	Terbutaline decreases the expression of Corticoliberin (CRH).	[10]
Tetrodotoxin	DMWMPRG	Approved	Tetrodotoxin decreases the activity of Corticoliberin (CRH).	[11]
Promazine	DMZAL7W	Approved	Promazine decreases the expression of Corticoliberin (CRH).	[8]
Meglitinides	DM1OFHN	Approved	Meglitinides decreases the expression of Corticoliberin (CRH).	[8]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Corticoliberin (CRH).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Corticoliberin (CRH).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Corticoliberin (CRH).	[13]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Forskolin	DM6ITNG	Investigative	Forskolin increases the secretion of Corticoliberin (CRH).	[14]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the secretion of Corticoliberin (CRH).	[15]

References

• [1] Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. Ann Neurol. 2005 Dec;58(6):899-904. doi: 10.1002/ana.20660.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [8] Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. Neuropsychopharmacology. 2006 Apr;31(4):853-65. doi: 10.1038/sj.npp.1300911.
• [9] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [10] Terbutaline inhibits corticotropin-releasing hormone (CRH) expression in human trophoblast cells. J Matern Fetal Neonatal Med. 2006 Nov;19(11):735-9. doi: 10.1080/14767050600886724.
• [11] Actions of endothelin and corticotropin releasing factor in the guinea-pig ileum: no evidence for an interaction with capsaicin-sensitive neurons. Neuropeptides. 2003 Aug;37(4):220-32. doi: 10.1016/s0143-4179(03)00048-9.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] 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.
• [14] Exposure to perfluorobutane sulfonate and perfluorooctanesulfonic acid disrupts the production of angiogenesis factors and stress responses in human placental syncytiotrophoblast. Reprod Toxicol. 2020 Dec;98:269-277. doi: 10.1016/j.reprotox.2020.10.013. Epub 2020 Nov 2.
• [15] Evidence for a functional link between the heme oxygenase-carbon monoxide pathway and corticotropin-releasing hormone release from primary cultures of human trophoblast cells. J Clin Endocrinol Metab. 2001 Jan;86(1):317-23. doi: 10.1210/jcem.86.1.7091.
• [16] Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts. J Mol Endocrinol. 2006 Dec;37(3):533-40.
• [17] Influence of cocaine dependence and early life stress on pituitary-adrenal axis responses to CRH and the Trier social stressor. Psychoneuroendocrinology. 2010 Nov;35(10):1492-500. doi: 10.1016/j.psyneuen.2010.05.001. Epub 2010 May 31.