Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGEDDM2)

• DOT Name: Aflatoxin B1 aldehyde reductase member 2 (AKR7A2)
• Synonyms: EC 1.1.1.n11; AFB1 aldehyde reductase 1; AFB1-AR 1; Aldoketoreductase 7; Succinic semialdehyde reductase; SSA reductase
• Gene Name: AKR7A2
• UniProt ID: ARK72_HUMAN
• PDB ID: 2BP1
• EC Number: 1.1.1.n11
• Pfam ID: PF00248
• Sequence:
  MLSAASRVVSRAAVHCALRSPPPEARALAMSRPPPPRVASVLGTMEMGRRMDAPASAAAV
  RAFLERGHTELDTAFMYSDGQSETILGGLGLGLGGGDCRVKIATKANPWDGKSLKPDSVR
  SQLETSLKRLQCPQVDLFYLHAPDHGTPVEETLHACQRLHQEGKFVELGLSNYASWEVAE
  ICTLCKSNGWILPTVYQGMYNATTRQVETELFPCLRHFGLRFYAYNPLAGGLLTGKYKYE
  DKDGKQPVGRFFGNSWAETYRNRFWKEHHFEAIALVEKALQAAYGASAPSVTSAALRWMY
  HHSQLQGAHGDAVILGMSSLEQLEQNLAATEEGPLEPAVVDAFNQAWHLVAHECPNYFR
• Function: Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate. May have an important role in producing the neuromodulator gamma-hydroxybutyrate (GHB). Has broad substrate specificity. Has NADPH-dependent aldehyde reductase activity towards 2-carboxybenzaldehyde, 2-nitrobenzaldehyde and pyridine-2-aldehyde (in vitro). Can reduce 1,2-naphthoquinone and 9,10-phenanthrenequinone (in vitro). Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.
• Tissue Specificity: Detected in brain, liver, small intestine and testis, and at lower levels in heart, prostate, skeletal muscle and spleen. Detected in kidney proximal and distal tubules, endothelial cells lining the Bowman's capsules and some cysts. Detected at low levels in lung and pancreas (at protein level). Widely expressed.
• KEGG Pathway: Metabolism of xenobiotics by cytochrome P450 (hsa00980)
• Reactome Pathway: Aflatoxin activation and detoxification (R-HSA-5423646)
• BioCyc Pathway: MetaCyc:ENSG00000053371-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Aflatoxin B1 aldehyde reductase member 2 (AKR7A2) increases the response to substance of Hydrogen peroxide.	[14]
Menadione	DMSJDTY	Approved	Aflatoxin B1 aldehyde reductase member 2 (AKR7A2) decreases the response to substance of Menadione.	[15]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenanthrene-9,10-dione	DMG8KS9	Investigative	Aflatoxin B1 aldehyde reductase member 2 (AKR7A2) increases the reduction of Phenanthrene-9,10-dione.	[16]
1,2-NAPHTHOQUINONE	DMYXELH	Investigative	Aflatoxin B1 aldehyde reductase member 2 (AKR7A2) increases the reduction of 1,2-NAPHTHOQUINONE.	[16]
1H-Indole-2,3-dione	DMOZ91H	Investigative	Aflatoxin B1 aldehyde reductase member 2 (AKR7A2) increases the reduction of 1H-Indole-2,3-dione.	[16]

12 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 Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[7]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[8]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[10]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal increases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[11]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal increases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[12]
7-hydroxycoumarin	DMTMNO7	Investigative	7-hydroxycoumarin increases the expression of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aflatoxin B1 aldehyde reductase member 2 (AKR7A2).	[9]

References

• [1] 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.
• [2] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [3] Insights into the transcriptional regulation of the anthracycline reductase AKR7A2 in human cardiomyocytes. Toxicol Lett. 2019 Jun 1;307:11-16.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [8] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [9] 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.
• [10] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [11] Protective effect of inducible aldo-keto reductases on 4-hydroxynonenal- induced hepatotoxicity. Chem Biol Interact. 2019 May 1;304:124-130.
• [12] Nrf2-mediated adaptive response to methyl glyoxal in HepG2 cells involves the induction of AKR7A2. Chem Biol Interact. 2015 Jun 5;234:366-71.
• [13] Hepatoprotective effect of 7-hydroxycoumarin against methyl glyoxal toxicity via activation of Nrf2. Chem Biol Interact. 2017 Oct 1;276:203-209.
• [14] Inducible protection of human astrocytoma 1321N1 cells against hydrogen peroxide and aldehyde toxicity by 7-hydroxycoumarin is associated with the upregulation of aldo-keto reductases. Neurotoxicology. 2012 Oct;33(5):1368-74.
• [15] Human aldo-keto reductase AKR7A2 protects against the cytotoxicity and mutagenicity of reactive aldehydes and lowers intracellular reactive oxygen species in hamster V79-4 cells. Chem Biol Interact. 2012 Jan 5;195(1):25-34. doi: 10.1016/j.cbi.2011.09.007. Epub 2011 Oct 5.
• [16] Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members. Biochem J. 1999 Oct 15;343 Pt 2(Pt 2):487-504.