Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNPDXG2)

• DOT Name: Retinoic acid receptor RXR-beta (RXRB)
• Synonyms: Nuclear receptor subfamily 2 group B member 2; Retinoid X receptor beta
• Gene Name: RXRB
• UniProt ID: RXRB_HUMAN
• PDB ID: 1H9U; 1UHL; 5HJP; 5I4V; 5KYA; 5KYJ; 7A78
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MSWAARPPFLPQRHAAGQCGPVGVRKEMHCGVASRWRRRRPWLDPAAAAAAAVAGGEQQT
  PEPEPGEAGRDGMGDSGRDSRSPDSSSPNPLPQGVPPPSPPGPPLPPSTAPSLGGSGAPP
  PPPMPPPPLGSPFPVISSSMGSPGLPPPAPPGFSGPVSSPQINSTVSLPGGGSGPPEDVK
  PPVLGVRGLHCPPPPGGPGAGKRLCAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLTYS
  CRDNKDCTVDKRQRNRCQYCRYQKCLATGMKREAVQEERQRGKDKDGDGEGAGGAPEEMP
  VDRILEAELAVEQKSDQGVEGPGGTGGSGSSPNDPVTNICQAADKQLFTLVEWAKRIPHF
  SSLPLDDQVILLRAGWNELLIASFSHRSIDVRDGILLATGLHVHRNSAHSAGVGAIFDRV
  LTELVSKMRDMRMDKTELGCLRAIILFNPDAKGLSNPSEVEVLREKVYASLETYCKQKYP
  EQQGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQLA
• Function: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE).
• Tissue Specificity: Expressed in aortic endothelial cells (at protein level) . Expressed in monocytes . Expressed in a variety of tumor cell lines.
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Th17 cell differentiation (hsa04659)
  Thyroid hormone sig.ling pathway (hsa04919)
  Adipocytokine sig.ling pathway (hsa04920)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Thyroid cancer (hsa05216)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Gastric cancer (hsa05226)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Signaling by Retinoic Acid (R-HSA-5362517)
  NR1H2 & NR1H3 regulate gene expression linked to lipogenesis (R-HSA-9029558)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake (R-HSA-9031525)
  NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose (R-HSA-9031528)
  NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis (R-HSA-9623433)
  NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis (R-HSA-9632974)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Retinoic acid receptor RXR-beta (RXRB) affects the response to substance of Cisplatin.	[16]

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 Retinoic acid receptor RXR-beta (RXRB).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Retinoic acid receptor RXR-beta (RXRB).	[2]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Retinoic acid receptor RXR-beta (RXRB).	[4]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Retinoic acid receptor RXR-beta (RXRB).	[6]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Retinoic acid receptor RXR-beta (RXRB).	[7]
Lindane	DMB8CNL	Approved	Lindane increases the activity of Retinoic acid receptor RXR-beta (RXRB).	[8]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Retinoic acid receptor RXR-beta (RXRB).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Retinoic acid receptor RXR-beta (RXRB).	[11]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Retinoic acid receptor RXR-beta (RXRB).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Retinoic acid receptor RXR-beta (RXRB).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the activity of Retinoic acid receptor RXR-beta (RXRB).	[8]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Retinoic acid receptor RXR-beta (RXRB).	[15]
Tetramethylbutylphenol	DMW9CH2	Investigative	Tetramethylbutylphenol increases the activity of Retinoic acid receptor RXR-beta (RXRB).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Retinoic acid receptor RXR-beta (RXRB).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Retinoic acid receptor RXR-beta (RXRB).	[13]

8 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[5]
Bexarotene	DMOBIKY	Approved	Bexarotene affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[5]
Bezafibrate	DMZDCS0	Approved	Bezafibrate affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[5]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Eicosapentaenoic acid/docosa-hexaenoic acid affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[10]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[5]
	DM9CEI5		affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[10]
Phthalic Acid	DMF9T64	Investigative	Phthalic Acid affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[5]
Phytanic acid	DMSZ1RB	Investigative	Phytanic acid affects the binding of Retinoic acid receptor RXR-beta (RXRB).	[10]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] All trans retinoic acid nanodisks enhance retinoic acid receptor mediated apoptosis and cell cycle arrest in mantle cell lymphoma. Br J Haematol. 2010 Jul;150(2):158-69. doi: 10.1111/j.1365-2141.2010.08209.x. Epub 2010 May 9.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [5] Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor , , subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11.
• [6] 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.
• [7] Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology. J Invest Dermatol. 2009 Feb;129(2):329-39. doi: 10.1038/jid.2008.258. Epub 2008 Sep 4.
• [8] A two-hybrid yeast assay to quantify the effects of xenobiotics on retinoid X receptor-mediated gene expression. Toxicol Lett. 2008 Feb 15;176(3):198-206. doi: 10.1016/j.toxlet.2007.11.006. Epub 2007 Dec 3.
• [9] Androgen sensitivity related proteins in hormone-sensitive and hormone-insensitive prostate cancer cell lines treated by androgen antagonist bicalutamide. Neoplasma. 2001;48(5):419-24.
• [10] Photoaffinity labeling of human retinoid X receptor beta (RXRbeta) with 9-cis-retinoic acid: identification of phytanic acid, docosahexaenoic acid, and lithocholic acid as ligands for RXRbeta. Biochemistry. 2002 Apr 16;41(15):4883-90. doi: 10.1021/bi0121151.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [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.