Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLLZV3P)

• DOT Name: Endothelin receptor type B (EDNRB)
• Synonyms: ET-B; ET-BR; Endothelin receptor non-selective type
• Gene Name: EDNRB
• Related Disease:
  ABCD syndrome
  Waardenburg syndrome type 4A
  Waardenburg syndrome type 2
  Waardenburg-Shah syndrome
  Hirschsprung disease, susceptibility to, 2
• UniProt ID: EDNRB_HUMAN
• PDB ID: 5GLH; 5GLI; 5X93; 5XPR; 6IGK; 6IGL; 6LRY; 8HBD; 8HCX
• Pfam ID: PF00001
• Sequence:
  MQPPPSLCGRALVALVLACGLSRIWGEERGFPPDRATPLLQTAEIMTPPTKTLWPKGSNA
  SLARSLAPAEVPKGDRTAGSPPRTISPPPCQGPIEIKETFKYINTVVSCLVFVLGIIGNS
  TLLRIIYKNKCMRNGPNILIASLALGDLLHIVIDIPINVYKLLAEDWPFGAEMCKLVPFI
  QKASVGITVLSLCALSIDRYRAVASWSRIKGIGVPKWTAVEIVLIWVVSVVLAVPEAIGF
  DIITMDYKGSYLRICLLHPVQKTAFMQFYKTAKDWWLFSFYFCLPLAITAFFYTLMTCEM
  LRKKSGMQIALNDHLKQRREVAKTVFCLVLVFALCWLPLHLSRILKLTLYNQNDPNRCEL
  LSFLLVLDYIGINMASLNSCINPIALYLVSKRFKNCFKSCLCCWCQSFEEKQSLEEKQSC
  LKFKANDHGYDNFRSSNKYSSS
• Function: Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
• Tissue Specificity: Expressed in placental stem villi vessels, but not in cultured placental villi smooth muscle cells.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
  Melanogenesis (hsa04916)
  Relaxin sig.ling pathway (hsa04926)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ABCD syndrome	DISLORJ1	Definitive	Autosomal dominant	[1]
Waardenburg syndrome type 4A	DISSMGSQ	Strong	Autosomal dominant	[2]
Waardenburg syndrome type 2	DISVZBEV	Supportive	Autosomal dominant	[3]
Waardenburg-Shah syndrome	DISR8C6R	Supportive	Autosomal dominant	[4]
Hirschsprung disease, susceptibility to, 2	DISPTD6F	Limited	Unknown	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Endothelin receptor type B (EDNRB).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Endothelin receptor type B (EDNRB).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endothelin receptor type B (EDNRB).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Endothelin receptor type B (EDNRB).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Endothelin receptor type B (EDNRB).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Endothelin receptor type B (EDNRB).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Endothelin receptor type B (EDNRB).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Endothelin receptor type B (EDNRB).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Endothelin receptor type B (EDNRB).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Endothelin receptor type B (EDNRB).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Endothelin receptor type B (EDNRB).	[15]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Endothelin receptor type B (EDNRB).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Endothelin receptor type B (EDNRB).	[17]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Endothelin receptor type B (EDNRB).	[18]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Endothelin receptor type B (EDNRB).	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Endothelin receptor type B (EDNRB).	[18]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Endothelin receptor type B (EDNRB).	[9]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Endothelin receptor type B (EDNRB).	[19]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Endothelin receptor type B (EDNRB).	[9]
Fenoterol	DMIP3ZV	Approved	Fenoterol increases the expression of Endothelin receptor type B (EDNRB).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Endothelin receptor type B (EDNRB).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Endothelin receptor type B (EDNRB).	[12]
MK-2206	DMT1OZ6	Phase 2	MK-2206 increases the expression of Endothelin receptor type B (EDNRB).	[21]
Pifithrin-alpha	DM63OD7	Terminated	Pifithrin-alpha decreases the expression of Endothelin receptor type B (EDNRB).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Endothelin receptor type B (EDNRB).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Endothelin receptor type B (EDNRB).	[26]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Endothelin receptor type B (EDNRB).	[27]

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 Endothelin receptor type B (EDNRB).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Endothelin receptor type B (EDNRB).	[24]

References

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• [2] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [3] EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state. Hum Mutat. 2017 May;38(5):581-593. doi: 10.1002/humu.23206. Epub 2017 Mar 15.
• [4] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [5] ABCD syndrome is caused by a homozygous mutation in the EDNRB gene. Am J Med Genet. 2002 Mar 15;108(3):223-5. doi: 10.1002/ajmg.10172.
• [6] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
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• [9] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [10] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [14] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [15] Rosiglitazone attenuates endothelin-1-induced vasoconstriction by upregulating endothelial expression of endothelin B receptor. Hypertension. 2010 Jul;56(1):129-35. doi: 10.1161/HYPERTENSIONAHA.110.150375. Epub 2010 Jun 1.
• [16] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [19] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [20] beta2-Adrenoceptor agonist modulates endothelin-1 receptors in human isolated bronchi. Am J Respir Cell Mol Biol. 2006 Apr;34(4):410-6. doi: 10.1165/rcmb.2005-0091OC. Epub 2005 Dec 9.
• [21] Chemerin promotes the pathogenesis of preeclampsia by activating CMKLR1/p-Akt/CEBP axis and inducing M1 macrophage polarization. Cell Biol Toxicol. 2022 Aug;38(4):611-628. doi: 10.1007/s10565-021-09636-7. Epub 2021 Aug 16.
• [22] 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.
• [23] The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. J Biol Chem. 2009 Feb 13;284(7):4343-53. doi: 10.1074/jbc.M805570200. Epub 2008 Dec 18.
• [24] 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.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.