Details of Drug Off-Target (DOT)

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

• DOT Name: Retinol dehydrogenase 5 (RDH5)
• Synonyms: EC 1.1.1.209; EC 1.1.1.315; EC 1.1.1.53; 11-cis retinol dehydrogenase; 11-cis RDH; 11-cis RoDH; 9-cis retinol dehydrogenase; 9cRDH; Short chain dehydrogenase/reductase family 9C member 5
• Gene Name: RDH5
• Related Disease:
  Fundus albipunctatus
  RDH5-related retinopathy
• UniProt ID: RDH5_HUMAN
• EC Number: 1.1.1.209; 1.1.1.315; 1.1.1.53
• Pfam ID: PF00106
• Sequence:
  MWLPLLLGALLWAVLWLLRDRQSLPASNAFVFITGCDSGFGRLLALQLDQRGFRVLASCL
  TPSGAEDLQRVASSRLHTTLLDITDPQSVQQAAKWVEMHVKEAGLFGLVNNAGVAGIIGP
  TPWLTRDDFQRVLNVNTMGPIGVTLALLPLLQQARGRVINITSVLGRLAANGGGYCVSKF
  GLEAFSDSLRRDVAHFGIRVSIVEPGFFRTPVTNLESLEKTLQACWARLPPATQAHYGGA
  FLTKYLKMQQRIMNLICDPDLTKVSRCLEHALTARHPRTRYSPGWDAKLLWLPASYLPAS
  LVDAVLTWVLPKPAQAVY
• Function: Catalyzes the oxidation of cis-isomers of retinol, including 11-cis-, 9-cis-, and 13-cis-retinol in an NAD-dependent manner. Has no activity towards all-trans retinal. Plays a significant role in 11-cis retinol oxidation in the retinal pigment epithelium cells (RPE). Also recognizes steroids (androsterone, androstanediol) as its substrates.
• Tissue Specificity: Widely expressed. In the eye, abundant in the retinal pigment epithelium.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  RA biosynthesis pathway (R-HSA-5365859)
  Retinoid cycle disease events (R-HSA-2453864)
• BioCyc Pathway: MetaCyc:HS06003-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fundus albipunctatus	DISNICY6	Definitive	Semidominant	[1]
RDH5-related retinopathy	DISWZQ2C	Definitive	Autosomal recessive	[2]

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 dehydrogenase 5 (RDH5).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinol dehydrogenase 5 (RDH5).	[9]

6 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 dehydrogenase 5 (RDH5).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Retinol dehydrogenase 5 (RDH5).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Retinol dehydrogenase 5 (RDH5).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Retinol dehydrogenase 5 (RDH5).	[7]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Retinol dehydrogenase 5 (RDH5).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Retinol dehydrogenase 5 (RDH5).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [7] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [8] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.