Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSO67MI)

• DOT Name: Alcohol dehydrogenase class-3 (ADH5)
• Synonyms: EC 1.1.1.1; Alcohol dehydrogenase 5; Alcohol dehydrogenase class chi chain; Alcohol dehydrogenase class-III; Glutathione-dependent formaldehyde dehydrogenase; FALDH; FDH; GSH-FDH; EC 1.1.1.-; S-(hydroxymethyl)glutathione dehydrogenase; EC 1.1.1.284
• Gene Name: ADH5
• Related Disease: AMED syndrome, digenic
• UniProt ID: ADHX_HUMAN
• PDB ID: 1M6H; 1M6W; 1MA0; 1MC5; 1MP0; 1TEH; 2FZE; 2FZW; 3QJ5; 8GV3
• EC Number: 1.1.1.-; 1.1.1.1; 1.1.1.284
• Pfam ID: PF08240 ; PF00107
• Sequence:
  MANEVIKCKAAVAWEAGKPLSIEEIEVAPPKAHEVRIKIIATAVCHTDAYTLSGADPEGC
  FPVILGHEGAGIVESVGEGVTKLKAGDTVIPLYIPQCGECKFCLNPKTNLCQKIRVTQGK
  GLMPDGTSRFTCKGKTILHYMGTSTFSEYTVVADISVAKIDPLAPLDKVCLLGCGISTGY
  GAAVNTAKLEPGSVCAVFGLGGVGLAVIMGCKVAGASRIIGVDINKDKFARAKEFGATEC
  INPQDFSKPIQEVLIEMTDGGVDYSFECIGNVKVMRAALEACHKGWGVSVVVGVAASGEE
  IATRPFQLVTGRTWKGTAFGGWKSVESVPKLVSEYMSKKIKVDEFVTHNLSFDEINKAFE
  LMHSGKSIRTVVKI
• Function: Catalyzes the oxidation of long-chain primary alcohols and the oxidation of S-(hydroxymethyl) glutathione. Also oxidizes long chain omega-hydroxy fatty acids, such as 20-HETE, producing both the intermediate aldehyde, 20-oxoarachidonate and the end product, a dicarboxylic acid, (5Z,8Z,11Z,14Z)-eicosatetraenedioate. Class-III ADH is remarkably ineffective in oxidizing ethanol. Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.
• 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)
  Carbon metabolism (hsa01200)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway: Ethanol oxidation (R-HSA-71384)
• BioCyc Pathway: MetaCyc:HS10601-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AMED syndrome, digenic	DISCZC4L	Limited	Unknown	[1]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Alcohol dehydrogenase class-3 (ADH5) increases the oxidation of Ethanol.	[15]
Nitrosoglutathione	DMZ9WI4	Investigative	Alcohol dehydrogenase class-3 (ADH5) increases the reduction of Nitrosoglutathione.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Formaldehyde	DM7Q6M0	Investigative	Alcohol dehydrogenase class-3 (ADH5) increases the metabolism of Formaldehyde.	[16]
Octanol	DMBGHPE	Investigative	Alcohol dehydrogenase class-3 (ADH5) increases the metabolism of Octanol.	[17]

13 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 Alcohol dehydrogenase class-3 (ADH5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Alcohol dehydrogenase class-3 (ADH5).	[8]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Alcohol dehydrogenase class-3 (ADH5).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Alcohol dehydrogenase class-3 (ADH5).	[13]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Alcohol dehydrogenase class-3 (ADH5).	[14]

References

• [1] Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. Sci Adv. 2020 Dec 18;6(51):eabd7197. doi: 10.1126/sciadv.abd7197. Print 2020 Dec.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] 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.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] 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.
• [13] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [14] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.
• [15] The Janus face of alcohol dehydrogenase 3. Chem Biol Interact. 2009 Mar 16;178(1-3):29-35. doi: 10.1016/j.cbi.2008.10.050. Epub 2008 Nov 6.
• [16] Structure-function relationships in human Class III alcohol dehydrogenase (formaldehyde dehydrogenase). Chem Biol Interact. 2003 Feb 1;143-144:195-200. doi: 10.1016/s0009-2797(02)00203-x.
• [17] Effect of pentachlorophenol and 2,6-dichloro-4-nitrophenol on the activity of cDNA-expressed human alcohol and aldehyde dehydrogenases. Toxicol Lett. 2009 Dec 15;191(2-3):360-4. doi: 10.1016/j.toxlet.2009.10.003. Epub 2009 Oct 12.