Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEX44Z2)

• DOT Name: Membrane progestin receptor delta (PAQR6)
• Synonyms: mPR delta; Membrane progesterone P4 receptor delta; Membrane progesterone receptor delta; Progesterone and adipoQ receptor family member 6; Progestin and adipoQ receptor family member 6
• Gene Name: PAQR6
• Related Disease: Nephrolithiasis, calcium oxalate
• UniProt ID: PAQR6_HUMAN
• Pfam ID: PF03006
• Sequence:
  MLSLKLPQLLQVHQVPRVFWEDGIMSGYRRPTSSALDCVLSSFQMTNETVNIWTHFLPTW
  YFLWRLLALAGGPGFRAEPYHWPLLVFLLPACLYPFASCCAHTFSSMSPRMRHICYFLDY
  GALSLYSLGCAFPYAAYSMPASWLHGHLHQFFVPAAALNSFLCTGLSCYSRFLELESPGL
  SKVLRTGAFAYPFLFDNLPLFYRLGLCWGRGHGCGQEALSTSHGYHLFCALLTGFLFASH
  LPERLAPGRFDYIGHSHQLFHICAVLGTHFQLEAVLADMGSRRAWLATQEPALGLAGTVA
  TLVLAAAGNLLIIAAFTATLLRAPSTCPLLQGGPLEGGTQAKQQ
• Function: Plasma membrane progesterone (P4) receptor coupled to G proteins. Seems to act through a G(s) mediated pathway. Involved in neurosteroid inhibition of apoptosis. May be involved in regulating rapid P4 signaling in the nervous system. Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone.
• Tissue Specificity: Brain specific . Highly expressed in the hypothalamus, also expressed in forebrain, amygdala, corpus callosum and spinal cord .
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephrolithiasis, calcium oxalate	DIS5J79C	Limited	Genetic Variation	[1]

3 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 delta (PAQR6).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Membrane progestin receptor delta (PAQR6).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Membrane progestin receptor delta (PAQR6).	[8]

7 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 delta (PAQR6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Membrane progestin receptor delta (PAQR6).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Membrane progestin receptor delta (PAQR6).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Membrane progestin receptor delta (PAQR6).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Membrane progestin receptor delta (PAQR6).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Membrane progestin receptor delta (PAQR6).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Membrane progestin receptor delta (PAQR6).	[11]

References

• [1] A whole genome SNP genotyping by DNA microarray and candidate gene association study for kidney stone disease.BMC Med Genet. 2014 May 2;15:50. doi: 10.1186/1471-2350-15-50.
• [2] 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.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.