Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC3AOPX)

• DOT Name: All-trans-retinol 13,14-reductase (RETSAT)
• Synonyms: EC 1.3.99.23; All-trans-13,14-dihydroretinol saturase; RetSat; PPAR-alpha-regulated and starvation-induced gene protein
• Gene Name: RETSAT
• Related Disease:
  Simpson-Golabi-Behmel syndrome type 1
  Fatty liver disease
  Hyperglycemia
• UniProt ID: RETST_HUMAN
• EC Number: 1.3.99.23
• Pfam ID: PF13450
• Sequence:
  MWLPLVLLLAVLLLAVLCKVYLGLFSGSSPNPFSEDVKRPPAPLVTDKEARKKVLKQAFS
  ANQVPEKLDVVVIGSGFGGLAAAAILAKAGKRVLVLEQHTKAGGCCHTFGKNGLEFDTGI
  HYIGRMEEGSIGRFILDQITEGQLDWAPLSSPFDIMVLEGPNGRKEYPMYSGEKAYIQGL
  KEKFPQEEAIIDKYIKLVKVVSSGAPHAILLKFLPLPVVQLLDRCGLLTRFSPFLQASTQ
  SLAEVLQQLGASSELQAVLSYIFPTYGVTPNHSAFSMHALLVNHYMKGGFYPRGGSSEIA
  FHTIPVIQRAGGAVLTKATVQSVLLDSAGKACGVSVKKGHELVNIYCPIVVSNAGLFNTY
  EHLLPGNARCLPGVKQQLGTVRPGLGMTSVFICLRGTKEDLHLPSTNYYVYYDTDMDQAM
  ERYVSMPREEAAEHIPLLFFAFPSAKDPTWEDRFPGRSTMIMLIPTAYEWFEEWQAELKG
  KRGSDYETFKNSFVEASMSVVLKLFPQLEGKVESVTAGSPLTNQFYLAAPRGACYGADHD
  LGRLHPCVMASLRAQSPIPNLYLTGQDIFTCGLVGALQGALLCSSAILKRNLYSDLKNLD
  SRIRAQKKKN
• Function: Catalyzes the saturation of all-trans-retinol to all-trans-13,14-dihydroretinol. Does not exhibit any activity toward all-trans-retinoic acid, nor 9-cis, 11-cis or 13-cis-retinol isomers. May play a role in the metabolism of vitamin A. Independently of retinol conversion, may regulate liver metabolism upstream of MLXIPL/ChREBP. May play a role in adipocyte differentiation.
• Tissue Specificity: Expressed in liver; expression positively correlates with obesity and liver steatosis . Expressed in adipose tissue; expression tends to be decreased in obese versus lean individuals .
• KEGG Pathway: Retinol metabolism (hsa00830)
• Reactome Pathway: Retinoid metabolism and transport (R-HSA-975634)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Simpson-Golabi-Behmel syndrome type 1	DISYV73N	Strong	Biomarker	[1]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[2]

15 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 All-trans-retinol 13,14-reductase (RETSAT).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[12]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[13]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of All-trans-retinol 13,14-reductase (RETSAT).	[17]

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 decreases the methylation of All-trans-retinol 13,14-reductase (RETSAT).	[14]

References

• [1] Retinol saturase promotes adipogenesis and is downregulated in obesity.Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1105-10. doi: 10.1073/pnas.0812065106. Epub 2009 Jan 12.
• [2] Retinol saturase coordinates liver metabolism by regulating ChREBP activity.Nat Commun. 2017 Aug 30;8(1):384. doi: 10.1038/s41467-017-00430-w.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] 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.
• [10] 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.
• [11] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.