Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ90CN4)

• DOT Name: Erythropoietin (EPO)
• Synonyms: Epoetin
• Gene Name: EPO
• Related Disease:
  Erythrocytosis, familial, 5
  Obsolete autosomal dominant secondary polycythemia
  Diamond-Blackfan anemia-like
• UniProt ID: EPO_HUMAN
• PDB ID: 1BUY; 1CN4; 1EER
• Pfam ID: PF00758
• Sequence:
  MGVHECPAWLWLLLSLLSLPLGLPVLGAPPRLICDSRVLERYLLEAKEAENITTGCAEHC
  SLNENITVPDTKVNFYAWKRMEVGQQAVEVWQGLALLSEAVLRGQALLVNSSQPWEPLQL
  HVDKAVSGLRSLTTLLRALGAQKEAISPPDAASAAPLRTITADTFRKLFRVYSNFLRGKL
  KLYTGEACRTGDR
• Function: Hormone involved in the regulation of erythrocyte proliferation and differentiation and the maintenance of a physiological level of circulating erythrocyte mass. Binds to EPOR leading to EPOR dimerization and JAK2 activation thereby activating specific downstream effectors, including STAT1 and STAT3.
• Tissue Specificity: Produced by kidney or liver of adult mammals and by liver of fetal or neonatal mammals.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  HIF-1 sig.ling pathway (hsa04066)
  Efferocytosis (hsa04148)
  PI3K-Akt sig.ling pathway (hsa04151)
  JAK-STAT sig.ling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Signaling by Erythropoietin (R-HSA-9006335)
  Erythropoietin activates Phosphoinositide-3-kinase (PI3K) (R-HSA-9027276)
  Erythropoietin activates Phospholipase C gamma (PLCG) (R-HSA-9027277)
  Erythropoietin activates STAT5 (R-HSA-9027283)
  Erythropoietin activates RAS (R-HSA-9027284)
  Regulation of gene expression by Hypoxia-inducible Factor (R-HSA-1234158)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythrocytosis, familial, 5	DISGM9QM	Strong	Autosomal dominant	[1]
Obsolete autosomal dominant secondary polycythemia	DISKHT4L	Supportive	Autosomal dominant	[2]
Diamond-Blackfan anemia-like	DISJDJ46	Limited	Unknown	[3]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Erythropoietin (EPO) decreases the response to substance of Cisplatin.	[31]
Fluorouracil	DMUM7HZ	Approved	Erythropoietin (EPO) increases the response to substance of Fluorouracil.	[32]
Paclitaxel	DMLB81S	Approved	Erythropoietin (EPO) decreases the response to substance of Paclitaxel.	[33]
Dacarbazine	DMNPZL4	Approved	Erythropoietin (EPO) decreases the response to substance of Dacarbazine.	[34]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitrite	DMR5XT3	Investigative	Erythropoietin (EPO) increases the abundance of Nitrite.	[35]

30 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 Erythropoietin (EPO).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Erythropoietin (EPO).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Erythropoietin (EPO).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Erythropoietin (EPO).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Erythropoietin (EPO).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Erythropoietin (EPO).	[9]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Erythropoietin (EPO).	[8]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Erythropoietin (EPO).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Erythropoietin (EPO).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Erythropoietin (EPO).	[12]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of Erythropoietin (EPO).	[13]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Erythropoietin (EPO).	[14]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Erythropoietin (EPO).	[15]
Enalapril	DMNFUZR	Approved	Enalapril decreases the expression of Erythropoietin (EPO).	[16]
Fenoterol	DMIP3ZV	Approved	Fenoterol increases the expression of Erythropoietin (EPO).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Erythropoietin (EPO).	[18]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Erythropoietin (EPO).	[19]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the expression of Erythropoietin (EPO).	[20]
Sodium stibogluconate	DMH5MVE	Phase 2	Sodium stibogluconate decreases the expression of Erythropoietin (EPO).	[21]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Erythropoietin (EPO).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Erythropoietin (EPO).	[22]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Erythropoietin (EPO).	[22]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin increases the expression of Erythropoietin (EPO).	[24]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Erythropoietin (EPO).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Erythropoietin (EPO).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Erythropoietin (EPO).	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A affects the expression of Erythropoietin (EPO).	[28]
Chrysin	DM7V2LG	Investigative	Chrysin increases the expression of Erythropoietin (EPO).	[20]
Apigenin	DMI3491	Investigative	Apigenin increases the expression of Erythropoietin (EPO).	[20]
Formononetin	DM7WFZ8	Investigative	Formononetin increases the expression of Erythropoietin (EPO).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Erythropoietin (EPO).	[23]
Manganese	DMKT129	Investigative	Manganese increases the glycosylation of Erythropoietin (EPO).	[29]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] A Gain-of-Function Mutation in EPO in Familial Erythrocytosis. N Engl J Med. 2018 Mar 8;378(10):924-930. doi: 10.1056/NEJMoa1709064.
• [3] Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell. 2017 Mar 9;168(6):1053-1064.e15. doi: 10.1016/j.cell.2017.02.026.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Role of hydrogen peroxide in hypoxia-induced erythropoietin production. Biochem J. 1994 Oct 15;303 ( Pt 2)(Pt 2):507-10. doi: 10.1042/bj3030507.
• [8] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [9] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [10] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [11] Amphotericin B blunts erythropoietin response to anemia. J Infect Dis. 1990 Feb;161(2):348-51. doi: 10.1093/infdis/161.2.348.
• [12] Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine. Ann Intern Med. 1988 Mar;108(3):372-6. doi: 10.7326/0003-4819-108-3-372.
• [13] Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease. Blood. 2009 Nov 19;114(21):4639-44. doi: 10.1182/blood-2009-04-218040. Epub 2009 Sep 1.
• [14] Role of erythropoietin in cortisol-induced hypertension. J Hum Hypertens. 2000 Mar;14(3):195-8. doi: 10.1038/sj.jhh.1000959.
• [15] Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron. Am J Clin Nutr. 2006 Sep;84(3):580-6. doi: 10.1093/ajcn/84.3.580.
• [16] Worsening of anemia by angiotensin converting enzyme inhibitors and its prevention by antiestrogenic steroid in chronic hemodialysis patients. J Cardiovasc Pharmacol. 1989;13 Suppl 3:S27-30. doi: 10.1097/00005344-198900133-00007.
• [17] Fenoterol but not dobutamine increases erythropoietin production in humans. Clin Pharmacol Ther. 1997 Jun;61(6):669-76. doi: 10.1016/S0009-9236(97)90102-8.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Mol Pharmacol. 2006 Nov;70(5):1664-71. doi: 10.1124/mol.106.025817. Epub 2006 Jul 31.
• [20] The flavonoids induce the transcription of mRNA encoding erythropoietin in cultured embryonic stem cells via the accumulation of hypoxia-inducible factor-1. Chem Biol Interact. 2023 Sep 1;382:110609. doi: 10.1016/j.cbi.2023.110609. Epub 2023 Jun 20.
• [21] Serum erythropoietin concentration in anaemia of visceral leishmaniasis (kala-azar) before and during antimonial therapy. Br J Haematol. 1998 Mar;100(4):720-4. doi: 10.1046/j.1365-2141.1998.00624.x.
• [22] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [23] 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.
• [24] Normal erythropoietin response in chronic hepatitis C patients with ribavirin-induced anaemia. Antivir Ther. 2003 Feb;8(1):57-63.
• [25] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [26] 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.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Ochratoxin A upregulates biomarkers associated with hypoxia and transformation in human kidney cells. Toxicol In Vitro. 2019 Jun;57:211-216. doi: 10.1016/j.tiv.2019.03.016. Epub 2019 Mar 12.
• [29] Amino acid and manganese supplementation modulates the glycosylation state of erythropoietin in a CHO culture system. Biotechnol Bioeng. 2007 Feb 15;96(3):538-49. doi: 10.1002/bit.21141.
• [30] Flavonoids from Radix Astragali induce the expression of erythropoietin in cultured cells: a signaling mediated via the accumulation of hypoxia-inducible factor-1. J Agric Food Chem. 2011 Mar 9;59(5):1697-704. doi: 10.1021/jf104018u. Epub 2011 Feb 10.
• [31] Contrasting effect of recombinant human erythropoietin on breast cancer cell response to cisplatin induced cytotoxicity. Radiol Oncol. 2012 Sep;46(3):213-25. doi: 10.2478/v10019-012-0037-8. Epub 2012 Jun 19.
• [32] Recombinant human erythropoietin alpha targets intratumoral blood vessels, improving chemotherapy in human xenograft models. Cancer Res. 2005 Aug 15;65(16):7186-93. doi: 10.1158/0008-5472.CAN-04-2498.
• [33] Erythropoietin protects sensory axons against paclitaxel-induced distal degeneration. Neurobiol Dis. 2006 Dec;24(3):525-30. doi: 10.1016/j.nbd.2006.08.014. Epub 2006 Sep 28.
• [34] Functional erythropoietin autocrine loop in melanoma. Am J Pathol. 2005 Mar;166(3):823-30. doi: 10.1016/S0002-9440(10)62303-6.
• [35] Protective action of erythropoietin on neuronal damage induced by activated microglia. FEBS J. 2013 Apr;280(7):1630-42. doi: 10.1111/febs.12172. Epub 2013 Mar 1.