Details of Drug Off-Target (DOT)

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

• DOT Name: Retinol dehydrogenase 12 (RDH12)
• Synonyms: EC 1.1.1.300; All-trans and 9-cis retinol dehydrogenase; Short chain dehydrogenase/reductase family 7C member 2
• Gene Name: RDH12
• Related Disease:
  Disorder of orbital region
  Leber congenital amaurosis 13
  RDH12-related recessive retinopathy
  Retinopathy
  Blindness
  Cone-rod dystrophy 2
  Eye disorder
  Fundus albipunctatus
  Leber congenital amaurosis 1
  Retinal degeneration
  Leber congenital amaurosis
  Retinitis pigmentosa
  Cone-rod dystrophy
  Inherited retinal dystrophy
• UniProt ID: RDH12_HUMAN
• EC Number: 1.1.1.300
• Pfam ID: PF00106
• Sequence:
  MLVTLGLLTSFFSFLYMVAPSIRKFFAGGVCRTNVQLPGKVVVITGANTGIGKETARELA
  SRGARVYIACRDVLKGESAASEIRVDTKNSQVLVRKLDLSDTKSIRAFAEGFLAEEKQLH
  ILINNAGVMMCPYSKTADGFETHLGVNHLGHFLLTYLLLERLKVSAPARVVNVSSVAHHI
  GKIPFHDLQSEKRYSRGFAYCHSKLANVLFTRELAKRLQGTGVTTYAVHPGVVRSELVRH
  SSLLCLLWRLFSPFVKTAREGAQTSLHCALAEGLEPLSGKYFSDCKRTWVSPRARNNKTA
  ERLWNVSCELLGIRWE
• Function: Retinoids dehydrogenase/reductase with a clear preference for NADP. Displays high activity towards 9-cis, 11-cis and all-trans-retinal. Shows very weak activity towards 13-cis-retinol. Also exhibits activity, albeit with lower affinity than for retinaldehydes, towards lipid peroxidation products (C9 aldehydes) such as 4-hydroxynonenal and trans-2-nonenal. May play an important function in photoreceptor cells to detoxify 4-hydroxynonenal and potentially other toxic aldehyde products resulting from lipid peroxidation. Has no dehydrogenase activity towards steroids.
• Tissue Specificity: Widely expressed, mostly in retina, kidney, brain, skeletal muscle, pancreas and stomach.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  Retinoid cycle disease events (R-HSA-2453864)
• BioCyc Pathway: MetaCyc:ENSG00000139988-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disorder of orbital region	DISH0ECJ	Definitive	Biomarker	[1]
Leber congenital amaurosis 13	DIS8BHC8	Definitive	Autosomal recessive	[2]
RDH12-related recessive retinopathy	DISB2MOW	Definitive	Autosomal recessive	[3]
Retinopathy	DISB4B0F	Definitive	Biomarker	[4]
Blindness	DISTIM10	Strong	Genetic Variation	[5]
Cone-rod dystrophy 2	DISX2RWY	Strong	Biomarker	[6]
Eye disorder	DISB52BH	Strong	CausalMutation	[7]
Fundus albipunctatus	DISNICY6	Strong	Genetic Variation	[7]
Leber congenital amaurosis 1	DISY2B33	Strong	Genetic Variation	[8]
Retinal degeneration	DISM1JHQ	Strong	Biomarker	[9]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[10]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[11]
Cone-rod dystrophy	DISY9RWN	Limited	Biomarker	[6]
Inherited retinal dystrophy	DISGGL77	Limited	Genetic Variation	[12]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin A	DMJ2AH4	Approved	Retinol dehydrogenase 12 (RDH12) increases the chemical synthesis of Vitamin A.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
All-trans-retinal	DM6CEVB	Investigative	Retinol dehydrogenase 12 (RDH12) increases the metabolism of All-trans-retinal.	[9]

6 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 Retinol dehydrogenase 12 (RDH12).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Retinol dehydrogenase 12 (RDH12).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Retinol dehydrogenase 12 (RDH12).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Retinol dehydrogenase 12 (RDH12).	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Retinol dehydrogenase 12 (RDH12).	[18]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Retinol dehydrogenase 12 (RDH12).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Retinol dehydrogenase 12 (RDH12).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Retinol dehydrogenase 12 (RDH12).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Retinol dehydrogenase 12 (RDH12).	[17]

References

• [1] Retinol dehydrogenase 12 (RDH12): Role in vision, retinal disease and future perspectives.Exp Eye Res. 2019 Nov;188:107793. doi: 10.1016/j.exer.2019.107793. Epub 2019 Sep 7.
• [2] RDH12 retinopathy: novel mutations and phenotypic description. Mol Vis. 2011;17:2706-16. Epub 2011 Oct 19.
• [3] 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.
• [4] Phenotype-genotype correlation with Sanger sequencing identified retinol dehydrogenase 12 (RDH12) compound heterozygous variants in a Chinese family with Leber congenital amaurosis.J Zhejiang Univ Sci B. 2017 May;18(5):421-429. doi: 10.1631/jzus.B1600156.
• [5] Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa. Arch Ophthalmol. 2008 Sep;126(9):1301-7. doi: 10.1001/archopht.126.9.1301.
• [6] RDH12 Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function.Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):5225-5236. doi: 10.1167/iovs.18-24708.
• [7] Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy.Nat Genet. 2004 Aug;36(8):850-4. doi: 10.1038/ng1394. Epub 2004 Jul 18.
• [8] A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy.Ophthalmic Genet. 2019 Apr;40(2):110-117. doi: 10.1080/13816810.2019.1582069. Epub 2019 Mar 14.
• [9] Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Hum Mol Genet. 2005 Dec 15;14(24):3865-75. doi: 10.1093/hmg/ddi411. Epub 2005 Nov 3.
• [10] Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis. Am J Hum Genet. 2004 Oct;75(4):639-46. doi: 10.1086/424889. Epub 2004 Aug 20.
• [11] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [12] PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY.Retina. 2019 Oct;39(10):2040-2052. doi: 10.1097/IAE.0000000000002242.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [19] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [20] 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.
• [21] Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Hum Mol Genet. 2005 Dec 15;14(24):3865-75. doi: 10.1093/hmg/ddi411. Epub 2005 Nov 3.