Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9G6SF0)

• DOT Name: Carbonyl reductase 3 (CBR3)
• Synonyms: EC 1.1.1.184; NADPH-dependent carbonyl reductase 3; Quinone reductase CBR3; EC 1.6.5.10; Short chain dehydrogenase/reductase family 21C member 2
• Gene Name: CBR3
• UniProt ID: CBR3_HUMAN
• PDB ID: 2HRB
• EC Number: 1.1.1.184; 1.6.5.10
• Pfam ID: PF00106
• Sequence:
  MSSCSRVALVTGANRGIGLAIARELCRQFSGDVVLTARDVARGQAAVQQLQAEGLSPRFH
  QLDIDDLQSIRALRDFLRKEYGGLNVLVNNAAVAFKSDDPMPFDIKAEMTLKTNFFATRN
  MCNELLPIMKPHGRVVNISSLQCLRAFENCSEDLQERFHSETLTEGDLVDLMKKFVEDTK
  NEVHEREGWPNSPYGVSKLGVTVLSRILARRLDEKRKADRILVNACCPGPVKTDMDGKDS
  IRTVEEGAETPVYLALLPPDATEPQGQLVHDKVVQNW
• Function: Catalyzes the NADPH-dependent reduction of carbonyl compounds to their corresponding alcohols. Has low NADPH-dependent oxidoreductase activity. Acts on several orthoquinones, acts as well on non-quinone compounds, such as isatin or on the anticancer drug oracin. Best substrates for CBR3 is 1,2- naphthoquinone, hence could play a role in protection against cytotoxicity of exogenous quinones. Exerts activity toward ortho-quinones but not paraquinones. No endogenous substrate for CBR3 except isatin has been identified.
• Tissue Specificity: Detected in ovary, pancreas, intestine, colon, kidney, brain, thymus, lung, heart, liver, spleen, leukocyte, prostate and testis.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Phase I - Functionalization of compounds (R-HSA-211945)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Carbonyl reductase 3 (CBR3) affects the response to substance of Doxorubicin.	[14]
Daunorubicin	DMQUSBT	Approved	Carbonyl reductase 3 (CBR3) affects the response to substance of Daunorubicin.	[14]
Acetohexamide	DMR6N7H	Approved	Carbonyl reductase 3 (CBR3) increases the Metabolic disorder ADR of Acetohexamide.	[16]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Oxcarbazepine	DM5PU6O	Approved	Carbonyl reductase 3 (CBR3) increases the reduction of Oxcarbazepine.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Carbonyl reductase 3 (CBR3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Carbonyl reductase 3 (CBR3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Carbonyl reductase 3 (CBR3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Carbonyl reductase 3 (CBR3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Carbonyl reductase 3 (CBR3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Carbonyl reductase 3 (CBR3).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Carbonyl reductase 3 (CBR3).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Carbonyl reductase 3 (CBR3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Carbonyl reductase 3 (CBR3).	[9]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Carbonyl reductase 3 (CBR3).	[10]
Celastrol	DMWQIJX	Preclinical	Celastrol increases the expression of Carbonyl reductase 3 (CBR3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Carbonyl reductase 3 (CBR3).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Carbonyl reductase 3 (CBR3).	[10]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Carbonyl reductase 3 (CBR3).	[13]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] 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] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [10] Regulation of human carbonyl reductase 3 (CBR3; SDR21C2) expression by Nrf2 in cultured cancer cells. Biochemistry. 2010 Oct 5;49(39):8499-511.
• [11] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [12] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [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] Naturally occurring variants of human CBR3 alter anthracycline in vitro metabolism. J Pharmacol Exp Ther. 2010 Mar;332(3):755-63.
• [15] The role of carbonyl reducing enzymes in oxcarbazepine in vitro metabolism in man. Chem Biol Interact. 2014 Sep 5;220:241-7.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.