Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL9RBH5)

• DOT Name: Retinol-binding protein 4 (RBP4)
• Synonyms: Plasma retinol-binding protein; PRBP; RBP
• Gene Name: RBP4
• Related Disease:
  Progressive retinal dystrophy due to retinol transport defect
  Microphthalmia, isolated, with coloboma 10
  Microphthalmia, isolated, with coloboma
• UniProt ID: RET4_HUMAN
• PDB ID: 1BRP; 1BRQ; 1JYD; 1JYJ; 1QAB; 1RBP; 1RLB; 2WQ9; 2WQA; 2WR6; 3BSZ; 3FMZ; 4O9S; 4PSQ; 5NTY; 5NU2; 5NU6; 5NU7; 5NU8; 5NU9; 5NUA; 5NUB; 6QBA
• Pfam ID: PF00061
• Sequence:
  MKWVWALLLLAALGSGRAERDCRVSSFRVKENFDKARFSGTWYAMAKKDPEGLFLQDNIV
  AEFSVDETGQMSATAKGRVRLLNNWDVCADMVGTFTDTEDPAKFKMKYWGVASFLQKGND
  DHWIVDTDYDTYAVQYSCRLLNLDGTCADSYSFVFSRDPNGLPPEAQKIVRQRQEELCLA
  RQYRLIVHNGYCDGRSERNLL
• Function: Retinol-binding protein that mediates retinol transport in blood plasma. Delivers retinol from the liver stores to the peripheral tissues (Probable). Transfers the bound all-trans retinol to STRA6, that then facilitates retinol transport across the cell membrane.
• Tissue Specificity: Detected in blood plasma and in urine (at protein level).
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  Retinoid metabolism disease events (R-HSA-6809583)
  Retinoid metabolism and transport (R-HSA-975634)
  Retinoid cycle disease events (R-HSA-2453864)
• BioCyc Pathway: MetaCyc:ENSG00000138207-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Progressive retinal dystrophy due to retinol transport defect	DISBFZO9	Definitive	Autosomal recessive	[1]
Microphthalmia, isolated, with coloboma 10	DIS3YW7N	Strong	Autosomal dominant	[2]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	Retinol-binding protein 4 (RBP4) increases the abundance of D-glucose.	[18]

2 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 Retinol-binding protein 4 (RBP4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinol-binding protein 4 (RBP4).	[16]

11 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 Retinol-binding protein 4 (RBP4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Retinol-binding protein 4 (RBP4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Retinol-binding protein 4 (RBP4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Retinol-binding protein 4 (RBP4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Retinol-binding protein 4 (RBP4).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Retinol-binding protein 4 (RBP4).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Retinol-binding protein 4 (RBP4).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Retinol-binding protein 4 (RBP4).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Retinol-binding protein 4 (RBP4).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Retinol-binding protein 4 (RBP4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Retinol-binding protein 4 (RBP4).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the binding of Retinol-binding protein 4 (RBP4).	[5]
Vitamin A	DMJ2AH4	Approved	Vitamin A affects the binding of Retinol-binding protein 4 (RBP4).	[5]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the binding of Retinol-binding protein 4 (RBP4).	[14]

References

• [1] Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis. Invest Ophthalmol Vis Sci. 1999 Jan;40(1):3-11.
• [2] Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease. Cell. 2015 Apr 23;161(3):634-646. doi: 10.1016/j.cell.2015.03.006.
• [3] 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.
• [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] Comparative ligand-binding analysis of ten human lipocalins. Biochim Biophys Acta. 2006 Feb;1764(2):161-73. doi: 10.1016/j.bbapap.2005.12.006. Epub 2006 Jan 6.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Raised serum, adipocyte, and adipose tissue retinol-binding protein 4 in overweight women with polycystic ovary syndrome: effects of gonadal and adrenal steroids. J Clin Endocrinol Metab. 2007 Jul;92(7):2764-72. doi: 10.1210/jc.2007-0091. Epub 2007 Apr 24.
• [10] 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.
• [11] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [12] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [13] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [14] Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. J Med Chem. 2011 Jul 14;54(13):4378-87. doi: 10.1021/jm200256g. Epub 2011 Jun 7.
• [15] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [16] 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.
• [17] 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.
• [18] Retinol binding protein 4 mediates MEHP-induced glucometabolic abnormalities in HepG2 cells. Toxicology. 2019 Aug 1;424:152236. doi: 10.1016/j.tox.2019.06.007. Epub 2019 Jun 20.