Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGZ8W9F)

• DOT Name: Membrane progestin receptor beta (PAQR8)
• Synonyms: mPR beta; Lysosomal membrane protein in brain 1; Membrane progesterone P4 receptor beta; Membrane progesterone receptor beta; Progesterone and adipoQ receptor family member 8; Progestin and adipoQ receptor family member 8; Progestin and adipoQ receptor family member VIII
• Gene Name: PAQR8
• Related Disease:
  Endometrial cancer
  Endometrial carcinoma
  Peripheral arterial disease
  Pituitary gland disorder
  Schizophrenia
• UniProt ID: PAQR8_HUMAN
• Pfam ID: PF03006
• Sequence:
  MTTAILERLSTLSVSGQQLRRLPKILEDGLPKMPCTVPETDVPQLFREPYIRTGYRPTGH
  EWRYYFFSLFQKHNEVVNVWTHLLAALAVLLRFWAFAEAEALPWASTHSLPLLLFILSSI
  TYLTCSLLAHLLQSKSELSHYTFYFVDYVGVSVYQYGSALAHFFYSSDQAWYDRFWLFFL
  PAAAFCGWLSCAGCCYAKYRYRRPYPVMRKICQVVPAGLAFILDISPVAHRVALCHLAGC
  QEQAAWYHTLQILFFLVSAYFFSCPVPEKYFPGSCDIVGHGHQIFHAFLSICTLSQLEAI
  LLDYQGRQEIFLQRHGPLSVHMACLSFFFLAACSAATAALLRHKVKARLTKKDS
• Function: Plasma membrane progesterone (P4) receptor coupled to G proteins. Seems to act through a G(i) mediated pathway. May be involved in oocyte maturation. Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone.
• Tissue Specificity: Highly expressed in the hypothalamus . Also expressed in spinal cord, kidney and testis.
• KEGG Pathway: Chemical carcinogenesis - receptor activation (hsa05207)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[1]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[1]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[2]
Pituitary gland disorder	DIS7XB48	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	No Known	Unknown	[4]

13 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 Membrane progestin receptor beta (PAQR8).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Membrane progestin receptor beta (PAQR8).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Membrane progestin receptor beta (PAQR8).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Membrane progestin receptor beta (PAQR8).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Membrane progestin receptor beta (PAQR8).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Membrane progestin receptor beta (PAQR8).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Membrane progestin receptor beta (PAQR8).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Membrane progestin receptor beta (PAQR8).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Membrane progestin receptor beta (PAQR8).	[13]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Membrane progestin receptor beta (PAQR8).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Membrane progestin receptor beta (PAQR8).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Membrane progestin receptor beta (PAQR8).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Membrane progestin receptor beta (PAQR8).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Membrane progestin receptor beta (PAQR8).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Membrane progestin receptor beta (PAQR8).	[16]

References

• [1] Membrane progesterone receptors and have potential as prognostic biomarkers of endometrial cancer.J Steroid Biochem Mol Biol. 2018 Apr;178:303-311. doi: 10.1016/j.jsbmb.2018.01.011. Epub 2018 Jan 17.
• [2] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [3] Involvement of Membrane Progestin Receptor Beta (mPR/Paqr8) in Sex Pheromone Progestin-Induced Expression of Luteinizing Hormone in the Pituitary of Male Chinese Black Sleeper (Bostrychus Sinensis).Front Endocrinol (Lausanne). 2018 Jul 18;9:397. doi: 10.3389/fendo.2018.00397. eCollection 2018.
• [4] De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014 Feb 13;506(7487):179-84. doi: 10.1038/nature12929. Epub 2014 Jan 22.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [18] 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.