Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZT9NOW)

• DOT Name: Aldo-keto reductase family 1 member A1 (AKR1A1)
• Synonyms: EC 1.1.1.2; EC 1.1.1.372; EC 1.1.1.54; Alcohol dehydrogenase ; Aldehyde reductase; Glucuronate reductase; EC 1.1.1.19; Glucuronolactone reductase; EC 1.1.1.20
• Gene Name: AKR1A1
• UniProt ID: AK1A1_HUMAN
• PDB ID: 2ALR
• EC Number: 1.1.1.19; 1.1.1.2; 1.1.1.20; 1.1.1.372; 1.1.1.54
• Pfam ID: PF00248
• Sequence:
  MAASCVLLHTGQKMPLIGLGTWKSEPGQVKAAVKYALSVGYRHIDCAAIYGNEPEIGEAL
  KEDVGPGKAVPREELFVTSKLWNTKHHPEDVEPALRKTLADLQLEYLDLYLMHWPYAFER
  GDNPFPKNADGTICYDSTHYKETWKALEALVAKGLVQALGLSNFNSRQIDDILSVASVRP
  AVLQVECHPYLAQNELIAHCQARGLEVTAYSPLGSSDRAWRDPDEPVLLEEPVVLALAEK
  YGRSPAQILLRWQVQRKVICIPKSITPSRILQNIKVFDFTFSPEEMKQLNALNKNWRYIV
  PMLTVDGKRVPRDAGHPLYPFNDPY
• Function: Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosaccharides and bile acids, with a preference for negatively charged substrates, such as glucuronate and succinic semialdehyde. Functions as a detoxifiying enzyme by reducing a range of toxic aldehydes. Reduces methylglyoxal and 3-deoxyglucosone, which are present at elevated levels under hyperglycemic conditions and are cytotoxic. Involved also in the detoxification of lipid-derived aldehydes like acrolein. Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). Displays no reductase activity towards retinoids.
• Tissue Specificity: Widely expressed. Highly expressed in kidney, salivary gland and liver. Detected in trachea, stomach, brain, lung, prostate, placenta, mammary gland, small intestine and lung.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Pentose and glucuro.te interconversions (hsa00040)
  Ascorbate and aldarate metabolism (hsa00053)
  Glycerolipid metabolism (hsa00561)
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Formation of xylulose-5-phosphate (R-HSA-5661270)
  Glutathione conjugation (R-HSA-156590)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 9 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of Doxorubicin.	[14]
Daunorubicin	DMQUSBT	Approved	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of Daunorubicin.	[14]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of 4-hydroxy-2-nonenal.	[15]
acrolein	DMAMCSR	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of acrolein.	[15]
methylglyoxal	DMRC3OZ	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of methylglyoxal.	[15]
1,2-NAPHTHOQUINONE	DMYXELH	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of 1,2-NAPHTHOQUINONE.	[15]
Phenylglyoxal	DMHW93J	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of Phenylglyoxal.	[15]
Nitrobenzaldehyde	DM4UHB5	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of Nitrobenzaldehyde.	[15]
BRN-0471734	DMZMWVX	Investigative	Aldo-keto reductase family 1 member A1 (AKR1A1) increases the reduction of BRN-0471734.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[3]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[1]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[8]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[10]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[12]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Aldo-keto reductase family 1 member A1 (AKR1A1).	[13]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] 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.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] 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.
• [6] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [10] 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.
• [11] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [12] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [13] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [14] Aldo-keto reductase 1C2 fails to metabolize doxorubicin and daunorubicin in vitro. Drug Metab Dispos. 2008 Jun;36(6):991-4. doi: 10.1124/dmd.108.020388. Epub 2008 Mar 5.
• [15] 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.