Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLY2CZM)

• DOT Name: Membrane progestin receptor epsilon (PAQR9)
• Synonyms: mPR epsilon; Membrane progesterone P4 receptor epsilon; Membrane progesterone receptor epsilon; Progesterone and adipoQ receptor family member 9; Progestin and adipoQ receptor family member 9; Progestin and adipoQ receptor family member IX
• Gene Name: PAQR9
• UniProt ID: PAQR9_HUMAN
• Pfam ID: PF03006
• Sequence:
  MPRRLQPRGAGTKGPPAPAPAASGAARNSHSAASRDPPASAKPLLRWDEVPDDFVECFIL
  SGYRRLPCTAQECLASVLKPTNETLNFWTHFIPLLLFLSKFCRLFFLSGGDVPFHHPWLL
  PLWCYASGVLLTFAMSCTAHVFSCLSLRLRAAFFYLDYASISYYGFGSTVAYYYYLLPGL
  SLLDARVMTPYLQQRLGWHVDCTRLIAAYRALVLPVAFVLAVACTVACCKSRTDWCTYPF
  ALRTFVFVMPLSMACPIMLESWLFDLRGENPTLFVHFYRRYFWLVVAAFFNVSKIPERIQ
  PGLFDIIGHSHQLFHIFTFLSIYDQVYYVEEGLRQFLQAPPAAPTFSGTVGYMLLLVVCL
  GLVIRKFLNSSEFCSKK
• Function: Plasma membrane progesterone (P4) receptor coupled to G proteins. Seems to act through a G(s) mediated pathway. May be involved in regulating rapid P4 signaling in the nervous system. Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone.
• Tissue Specificity: Expression levels vary widely in a range of tissues . Expressed in the brain, at high level in the pituitary gland and also in hypothalamus, limbic system, caudate nucleus accumens, pons and olfactory bulb .
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

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 Membrane progestin receptor epsilon (PAQR9).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Membrane progestin receptor epsilon (PAQR9).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Membrane progestin receptor epsilon (PAQR9).	[5]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[10]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Membrane progestin receptor epsilon (PAQR9).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Membrane progestin receptor epsilon (PAQR9).	[12]

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] 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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] 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.
• [6] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.