Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5PWHAI)

• DOT Name: Corticotropin-releasing factor receptor 1 (CRHR1)
• Synonyms: CRF-R-1; CRF-R1; CRFR-1; Corticotropin-releasing hormone receptor 1; CRH-R-1; CRH-R1
• Gene Name: CRHR1
• UniProt ID: CRFR1_HUMAN
• PDB ID: 2L27; 3EHS; 3EHT; 3EHU; 4K5Y; 4Z9G; 6P9X; 6PB0
• Pfam ID: PF00002 ; PF02793
• Sequence:
  MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPA
  GQLVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAV
  IINYLGHCISLVALLVAFVLFLRLRPGCTHWGDQADGALEVGAPWSGAPFQVRRSIRCLR
  NIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVGWCRLVTAAYNYFHVTNFFWMFGEGC
  YLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAIGKLYYDNEKCWFGKRPGVYTDYI
  YQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKAVKATLVLLPLLGITYMLFF
  VNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRKRWHRWQDKHSIRARV
  ARAMSIPTSPTRVSFHSIKQSTAV
• Function: G-protein coupled receptor for CRH (corticotropin-releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli.
• Tissue Specificity: Predominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe.
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

2 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 Corticotropin-releasing factor receptor 1 (CRHR1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Corticotropin-releasing factor receptor 1 (CRHR1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Corticotropin-releasing factor receptor 1 (CRHR1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Corticotropin-releasing factor receptor 1 (CRHR1).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Corticotropin-releasing factor receptor 1 (CRHR1).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Corticotropin-releasing factor receptor 1 (CRHR1).	[3]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Corticotropin-releasing factor receptor 1 (CRHR1).	[5]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Corticotropin-releasing factor receptor 1 (CRHR1).	[7]

References

• [1] 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.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Identification of a novel corticotropin-releasing hormone type 1beta-like receptor variant lacking Exon 13 in human pregnant myometrium regulated by estradiol-17beta and progesterone. Endocrinology. 2010 Oct;151(10):4959-68. doi: 10.1210/en.2010-0622. Epub 2010 Aug 11.
• [4] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [5] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.