Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ3A541)

• DOT Name: Carbonyl reductase 1 (CBR1)
• Synonyms: EC 1.1.1.184; 15-hydroxyprostaglandin dehydrogenase ; EC 1.1.1.196, EC 1.1.1.197; 20-beta-hydroxysteroid dehydrogenase; Alcohol dehydrogenase CBR1; EC 1.1.1.71; NADPH-dependent carbonyl reductase 1; Prostaglandin 9-ketoreductase; PG-9-KR; Prostaglandin-E(2) 9-reductase; EC 1.1.1.189; Short chain dehydrogenase/reductase family 21C member 1
• Gene Name: CBR1
• UniProt ID: CBR1_HUMAN
• PDB ID: 1WMA; 2PFG; 3BHI; 3BHJ; 3BHM; 4Z3D
• EC Number: 1.1.1.184; 1.1.1.189; 1.1.1.196; 1.1.1.197; 1.1.1.71
• Pfam ID: PF00106
• Sequence:
  MSSGIHVALVTGGNKGIGLAIVRDLCRLFSGDVVLTARDVTRGQAAVQQLQAEGLSPRFH
  QLDIDDLQSIRALRDFLRKEYGGLDVLVNNAGIAFKVADPTPFHIQAEVTMKTNFFGTRD
  VCTELLPLIKPQGRVVNVSSIMSVRALKSCSPELQQKFRSETITEEELVGLMNKFVEDTK
  KGVHQKEGWPSSAYGVTKIGVTVLSRIHARKLSEQRKGDKILLNACCPGWVRTDMAGPKA
  TKSPEEGAETPVYLALLPPDAEGPHGQFVSEKRVEQW
• Function: NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione. In addition, participates in the glucocorticoid metabolism by catalyzing the NADPH-dependent cortisol/corticosterone into 20beta-dihydrocortisol (20b-DHF) or 20beta-corticosterone (20b-DHB), which are weak agonists of NR3C1 and NR3C2 in adipose tissue.
• Tissue Specificity: Expressed in kidney (at protein level).
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Folate biosynthesis (hsa00790)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway: Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
• BioCyc Pathway: MetaCyc:HS08378-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Carbonyl reductase 1 (CBR1) decreases the metabolism of Doxorubicin.	[17]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Oxcarbazepine	DM5PU6O	Approved	Carbonyl reductase 1 (CBR1) increases the reduction of Oxcarbazepine.	[18]
Tiaprofenic acid	DM23D7J	Approved	Carbonyl reductase 1 (CBR1) increases the reduction of Tiaprofenic acid.	[19]
Nitrosoglutathione	DMZ9WI4	Investigative	Carbonyl reductase 1 (CBR1) increases the reduction of Nitrosoglutathione.	[21]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Carbonyl reductase 1 (CBR1) affects the binding of Resveratrol.	[20]

2 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 Carbonyl reductase 1 (CBR1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Carbonyl reductase 1 (CBR1).	[11]

16 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 Carbonyl reductase 1 (CBR1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbonyl reductase 1 (CBR1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Carbonyl reductase 1 (CBR1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Carbonyl reductase 1 (CBR1).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Carbonyl reductase 1 (CBR1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Carbonyl reductase 1 (CBR1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Carbonyl reductase 1 (CBR1).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Carbonyl reductase 1 (CBR1).	[9]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Carbonyl reductase 1 (CBR1).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Carbonyl reductase 1 (CBR1).	[10]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the activity of Carbonyl reductase 1 (CBR1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Carbonyl reductase 1 (CBR1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Carbonyl reductase 1 (CBR1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Carbonyl reductase 1 (CBR1).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Carbonyl reductase 1 (CBR1).	[16]
Aloe-emodin	DMPTY8S	Investigative	Aloe-emodin decreases the activity of Carbonyl reductase 1 (CBR1).	[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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [5] Carbonyl reductase 1 offers a novel therapeutic target to enhance leukemia treatment by arsenic trioxide. Cancer Res. 2012 Aug 15;72(16):4214-24.
• [6] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Inhibition of human carbonyl reducing enzymes by plant anthrone and anthraquinone derivatives. Chem Biol Interact. 2022 Feb 25;354:109823. doi: 10.1016/j.cbi.2022.109823. Epub 2022 Jan 21.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] 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.
• [17] Two nonsynonymous single nucleotide polymorphisms of human carbonyl reductase 1 demonstrate reduced in vitro metabolism of daunorubicin and doxorubicin. Drug Metab Dispos. 2009 May;37(5):1107-14. doi: 10.1124/dmd.108.024711. Epub 2009 Feb 9.
• [18] The role of carbonyl reducing enzymes in oxcarbazepine in vitro metabolism in man. Chem Biol Interact. 2014 Sep 5;220:241-7.
• [19] Reductive metabolism of tiaprofenic acid by the human liver and recombinant carbonyl reducing enzymes. Chem Biol Interact. 2017 Oct 1;276:121-126. doi: 10.1016/j.cbi.2017.03.006. Epub 2017 Mar 18.
• [20] Identification of carbonyl reductase 1 as a resveratrol-binding protein by affinity chromatography using 4'-amino-3,5-dihydroxy-trans-stilbene. J Nutr Sci Vitaminol (Tokyo). 2013;59(4):358-64. doi: 10.3177/jnsv.59.358.
• [21] Studies on reduction of S-nitrosoglutathione by human carbonyl reductases 1 and 3. Chem Biol Interact. 2011 May 30;191(1-3):95-103.