Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBE6WAC)

• DOT Name: Membrane-associated progesterone receptor component 1 (PGRMC1)
• Synonyms: mPR; Dap1; IZA
• Gene Name: PGRMC1
• UniProt ID: PGRC1_HUMAN
• PDB ID: 4X8Y
• Pfam ID: PF00173
• Sequence:
  MAAEDVVATGADPSDLESGGLLHEIFTSPLNLLLLGLCIFLLYKIVRGDQPAASGDSDDD
  EPPPLPRLKRRDFTPAELRRFDGVQDPRILMAINGKVFDVTKGRKFYGPEGPYGVFAGRD
  ASRGLATFCLDKEALKDEYDDLSDLTAAQQETLSDWESQFTFKYHHVGKLLKEGEEPTVY
  SDEEEPKDESARKND
• Function: Component of a progesterone-binding protein complex. Binds progesterone. Has many reported cellular functions (heme homeostasis, interaction with CYPs). Required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan. Intracellular heme chaperone. Regulates heme synthesis via interactions with FECH and acts as a heme donor for at least some hemoproteins. Forms a ternary complex with TMEM97 receptor and low density lipid receptor/LDLR, which increases LDLR-mediated LDL lipoprotein internalization.
• Tissue Specificity: Detected in urine (at protein level) . Expressed by endometrial glands and stroma (at protein level) . Widely expressed, with highest expression in liver and kidney.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Membrane-associated progesterone receptor component 1 (PGRMC1) affects the response to substance of Vinblastine.	[16]
Gefitinib	DM15F0X	Approved	Membrane-associated progesterone receptor component 1 (PGRMC1) decreases the response to substance of Gefitinib.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Membrane-associated progesterone receptor component 1 (PGRMC1).	[1]
Quercetin	DM3NC4M	Approved	Quercetin affects the phosphorylation of Membrane-associated progesterone receptor component 1 (PGRMC1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Membrane-associated progesterone receptor component 1 (PGRMC1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Membrane-associated progesterone receptor component 1 (PGRMC1).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Membrane-associated progesterone receptor component 1 (PGRMC1).	[8]

12 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-associated progesterone receptor component 1 (PGRMC1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[9]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[10]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Membrane-associated progesterone receptor component 1 (PGRMC1).	[15]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [11] 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.
• [12] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [17] Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance. Toxicol Appl Pharmacol. 2015 Nov 1;288(3):359-73. doi: 10.1016/j.taap.2015.08.008. Epub 2015 Aug 20.