Details of Drug Off-Target (DOT)

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

• DOT Name: All-trans-retinol dehydrogenase ADH4 (ADH4)
• Synonyms: EC 1.1.1.105; Alcohol dehydrogenase 2; Alcohol dehydrogenase 4; Alcohol dehydrogenase class II pi chain
• Gene Name: ADH4
• UniProt ID: ADH4_HUMAN
• PDB ID: 3COS
• EC Number: 1.1.1.105
• Pfam ID: PF08240 ; PF00107
• Sequence:
  MGTKGKVIKCKAAIAWEAGKPLCIEEVEVAPPKAHEVRIQIIATSLCHTDATVIDSKFEG
  LAFPVIVGHEAAGIVESIGPGVTNVKPGDKVIPLYAPLCRKCKFCLSPLTNLCGKISNLK
  SPASDQQLMEDKTSRFTCKGKPVYHFFGTSTFSQYTVVSDINLAKIDDDANLERVCLLGC
  GFSTGYGAAINNAKVTPGSTCAVFGLGGVGLSAVMGCKAAGASRIIGIDINSEKFVKAKA
  LGATDCLNPRDLHKPIQEVIIELTKGGVDFALDCAGGSETMKAALDCTTAGWGSCTFIGV
  AAGSKGLTIFPEELIIGRTINGTFFGGWKSVDSIPKLVTDYKNKKFNLDALVTHTLPFDK
  ISEAFDLMNQGKSVRTILIF
• Function: Catalyzes the NAD-dependent oxidation of either all-trans-retinol or 9-cis-retinol. 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. Also catalyzes the reduction of benzoquinones.
• 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)
  RA biosynthesis pathway (R-HSA-5365859)
• BioCyc Pathway: MetaCyc:HS06569-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Polyethylene glycol	DM4I1JP	Approved	All-trans-retinol dehydrogenase ADH4 (ADH4) increases the oxidation of Polyethylene glycol.	[14]
2-Propanol, Isopropanol	DML5O0H	Investigative	All-trans-retinol dehydrogenase ADH4 (ADH4) increases the oxidation of 2-Propanol, Isopropanol.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaldehyde	DMJFKG4	Investigative	All-trans-retinol dehydrogenase ADH4 (ADH4) increases the abundance of Acetaldehyde.	[15]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[8]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[13]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of All-trans-retinol dehydrogenase ADH4 (ADH4).	[5]

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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [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] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] 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.
• [15] Polymorphisms in the promoter region of the human class II alcohol dehydrogenase (ADH4) gene affect both transcriptional activity and ethanol metabolism in Japanese subjects. J Toxicol Sci. 2009 Feb;34(1):89-97. doi: 10.2131/jts.34.89.