Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3TB81)

• DOT Name: All-trans-retinol dehydrogenase ADH1B (ADH1B)
• Synonyms: EC 1.1.1.105; Alcohol dehydrogenase 1B; Alcohol dehydrogenase subunit beta
• Gene Name: ADH1B
• UniProt ID: ADH1B_HUMAN
• PDB ID: 1DEH; 1HDX; 1HDY; 1HDZ; 1HSZ; 1HTB; 1U3U; 1U3V; 3HUD
• EC Number: 1.1.1.105
• Pfam ID: PF08240 ; PF00107
• Sequence:
  MSTAGKVIKCKAAVLWEVKKPFSIEDVEVAPPKAYEVRIKMVAVGICHTDDHVVSGNLVT
  PLPVILGHEAAGIVESVGEGVTTVKPGDKVIPLFTPQCGKCRVCKNPESNYCLKNDLGNP
  RGTLQDGTRRFTCRGKPIHHFLGTSTFSQYTVVDENAVAKIDAASPLEKVCLIGCGFSTG
  YGSAVNVAKVTPGSTCAVFGLGGVGLSAVMGCKAAGAARIIAVDINKDKFAKAKELGATE
  CINPQDYKKPIQEVLKEMTDGGVDFSFEVIGRLDTMMASLLCCHEACGTSVIVGVPPASQ
  NLSINPMLLLTGRTWKGAVYGGFKSKEGIPKLVADFMAKKFSLDALITHVLPFEKINEGF
  DLLHSGKSIRTVLTF
• Function: Catalyzes the NAD-dependent oxidation of all-trans-retinol and its derivatives such as all-trans-4-hydroxyretinol and may participate in retinoid metabolism. In vitro can also catalyzes the NADH-dependent reduction of all-trans-retinal and its derivatives such as all-trans-4-oxoretinal. Catalyzes in the oxidative direction with higher efficiency. Has the same affinity for all-trans-4-hydroxyretinol and all-trans-4-oxoretinal.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Fatty acid degradation (hsa00071)
  Tyrosine metabolism (hsa00350)
  Pyruvate metabolism (hsa00620)
  Retinol metabolism (hsa00830)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway: Ethanol oxidation (R-HSA-71384)
• BioCyc Pathway: MetaCyc:MONOMER66-321

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	All-trans-retinol dehydrogenase ADH1B (ADH1B) increases the metabolism of Tretinoin.	[16]
All-trans-retinal	DM6CEVB	Investigative	All-trans-retinol dehydrogenase ADH1B (ADH1B) increases the metabolism of All-trans-retinal.	[16]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Polyethylene glycol	DM4I1JP	Approved	All-trans-retinol dehydrogenase ADH1B (ADH1B) increases the oxidation of Polyethylene glycol.	[17]
Acetaldehyde	DMJFKG4	Investigative	All-trans-retinol dehydrogenase ADH1B (ADH1B) increases the oxidation of Acetaldehyde.	[18]
2-Propanol, Isopropanol	DML5O0H	Investigative	All-trans-retinol dehydrogenase ADH1B (ADH1B) increases the oxidation of 2-Propanol, Isopropanol.	[17]

1 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 All-trans-retinol dehydrogenase ADH1B (ADH1B).	[1]

15 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 All-trans-retinol dehydrogenase ADH1B (ADH1B).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[3]
Selenium	DM25CGV	Approved	Selenium decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[9]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[10]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Flucloxacillin	DMNUWST	Approved	Flucloxacillin affects the binding of All-trans-retinol dehydrogenase ADH1B (ADH1B).	[12]

References

• [1] 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.
• [2] 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.
• [3] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [6] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] 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.
• [9] Differences in the activities of resveratrol and ascorbic acid in protection of ethanol-induced oxidative DNA damage in human peripheral lymphocytes. Food Chem Toxicol. 2012 Feb;50(2):168-74.
• [10] Thyroid hormone responsive genes in cultured human fibroblasts. J Clin Endocrinol Metab. 2005 Feb;90(2):936-43.
• [11] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [12] Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury. Toxicol Sci. 2023 Mar 20;192(1):106-116. doi: 10.1093/toxsci/kfad015.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism. Cell Mol Life Sci. 2007 Feb;64(4):498-505. doi: 10.1007/s00018-007-6449-8.
• [17] Oxidation of methanol, ethylene glycol, and isopropanol with human alcohol dehydrogenases and the inhibition by ethanol and 4-methylpyrazole. Chem Biol Interact. 2011 May 30;191(1-3):26-31. doi: 10.1016/j.cbi.2010.12.005. Epub 2010 Dec 15.
• [18] Inhibition of human alcohol and aldehyde dehydrogenases by cimetidine and assessment of its effects on ethanol metabolism. Chem Biol Interact. 2013 Feb 25;202(1-3):275-82. doi: 10.1016/j.cbi.2012.11.016. Epub 2012 Dec 7.