Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTHN46W)

• DOT Name: Prolactin receptor (PRLR)
• Synonyms: PRL-R
• Gene Name: PRLR
• Related Disease: Familial hyperprolactinemia
• UniProt ID: PRLR_HUMAN
• PDB ID: 1BP3; 2LFG; 2N7I; 3D48; 3MZG; 3N06; 3N0P; 3NCB; 3NCC; 3NCE; 3NCF; 4I18
• Pfam ID: PF09067
• Sequence:
  MKENVASATVFTLLLFLNTCLLNGQLPPGKPEIFKCRSPNKETFTCWWRPGTDGGLPTNY
  SLTYHREGETLMHECPDYITGGPNSCHFGKQYTSMWRTYIMMVNATNQMGSSFSDELYVD
  VTYIVQPDPPLELAVEVKQPEDRKPYLWIKWSPPTLIDLKTGWFTLLYEIRLKPEKAAEW
  EIHFAGQQTEFKILSLHPGQKYLVQVRCKPDHGYWSAWSPATFIQIPSDFTMNDTTVWIS
  VAVLSAVICLIIVWAVALKGYSMVTCIFPPVPGPKIKGFDAHLLEKGKSEELLSALGCQD
  FPPTSDYEDLLVEYLEVDDSEDQHLMSVHSKEHPSQGMKPTYLDPDTDSGRGSCDSPSLL
  SEKCEEPQANPSTFYDPEVIEKPENPETTHTWDPQCISMEGKIPYFHAGGSKCSTWPLPQ
  PSQHNPRSSYHNITDVCELAVGPAGAPATLLNEAGKDALKSSQTIKSREEGKATQQREVE
  SFHSETDQDTPWLLPQEKTPFGSAKPLDYVEIHKVNKDGALSLLPKQRENSGKPKKPGTP
  ENNKEYAKVSGVMDNNILVLVPDPHAKNVACFEESAKEAPPSLEQNQAEKALANFTATSS
  KCRLQLGGLDYLDPACFTHSFH
• Function: This is a receptor for the anterior pituitary hormone prolactin (PRL). Acts as a prosurvival factor for spermatozoa by inhibiting sperm capacitation through suppression of SRC kinase activation and stimulation of AKT. Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling.
• Tissue Specificity: Expressed in breast, placenta, kidney, liver and pancreas.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt sig.ling pathway (hsa04151)
  JAK-STAT sig.ling pathway (hsa04630)
  Prolactin sig.ling pathway (hsa04917)
• Reactome Pathway:
  Growth hormone receptor signaling (R-HSA-982772)
  Prolactin receptor signaling (R-HSA-1170546)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hyperprolactinemia	DIS5WERT	Supportive	Autosomal dominant	[1]

17 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 Prolactin receptor (PRLR).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prolactin receptor (PRLR).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prolactin receptor (PRLR).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Prolactin receptor (PRLR).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Prolactin receptor (PRLR).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Prolactin receptor (PRLR).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Prolactin receptor (PRLR).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Prolactin receptor (PRLR).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Prolactin receptor (PRLR).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Prolactin receptor (PRLR).	[11]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Prolactin receptor (PRLR).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Prolactin receptor (PRLR).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prolactin receptor (PRLR).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Prolactin receptor (PRLR).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Prolactin receptor (PRLR).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Prolactin receptor (PRLR).	[18]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Prolactin receptor (PRLR).	[19]

1 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 Prolactin receptor (PRLR).	[13]

References

• [1] Mutant prolactin receptor and familial hyperprolactinemia. N Engl J Med. 2013 Nov 21;369(21):2012-2020. doi: 10.1056/NEJMoa1307557. Epub 2013 Nov 6.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [5] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [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] Expression of estrogen-, progesterone-, and androgen-responsive genes in MCF-7 and MDA-MB-231 cells treated with o,p'-DDT, p,p'-DDT, or endosulfan. J Biochem Mol Toxicol. 2021 Jun;35(6):1-8. doi: 10.1002/jbt.22773. Epub 2021 Mar 16.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [16] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [17] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [18] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [19] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.