Details of Drug Off-Target (DOT)

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

• DOT Name: L-xylulose reductase (DCXR)
• Synonyms: XR; EC 1.1.1.10; Carbonyl reductase II; Dicarbonyl/L-xylulose reductase; Kidney dicarbonyl reductase; kiDCR; Short chain dehydrogenase/reductase family 20C member 1; Sperm surface protein P34H
• Gene Name: DCXR
• Related Disease: Pentosuria
• UniProt ID: DCXR_HUMAN
• PDB ID: 1PR9; 1WNT; 3D3W
• EC Number: 1.1.1.10
• Pfam ID: PF13561
• Sequence:
  MELFLAGRRVLVTGAGKGIGRGTVQALHATGARVVAVSRTQADLDSLVRECPGIEPVCVD
  LGDWEATERALGSVGPVDLLVNNAAVALLQPFLEVTKEAFDRSFEVNLRAVIQVSQIVAR
  GLIARGVPGAIVNVSSQCSQRAVTNHSVYCSTKGALDMLTKVMALELGPHKIRVNAVNPT
  VVMTSMGQATWSDPHKAKTMLNRIPLGKFAEVEHVVNAILFLLSDRSGMTTGSTLPVEGG
  FWAC
• Function: Catalyzes the NADPH-dependent reduction of several pentoses, tetroses, trioses, alpha-dicarbonyl compounds and L-xylulose. Participates in the uronate cycle of glucose metabolism. May play a role in the water absorption and cellular osmoregulation in the proximal renal tubules by producing xylitol, an osmolyte, thereby preventing osmolytic stress from occurring in the renal tubules.
• Tissue Specificity: Highly expressed in kidney, liver and epididymis. In the epididymis, it is mainly expressed in the proximal and distal sections of the corpus region. Weakly or not expressed in brain, lung, heart, spleen and testis.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Essential pentosuria (R-HSA-5662853)
  Formation of xylulose-5-phosphate (R-HSA-5661270)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pentosuria	DISB4DRV	Supportive	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	L-xylulose reductase (DCXR) increases the chemical synthesis of Hydrogen peroxide.	[25]

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Menadione	DMSJDTY	Approved	L-xylulose reductase (DCXR) increases the metabolism of Menadione.	[25]
1,4-Naphthoquinone	DMTCMH7	Investigative	L-xylulose reductase (DCXR) increases the metabolism of 1,4-Naphthoquinone.	[25]
Phenanthrene-9,10-dione	DMG8KS9	Investigative	L-xylulose reductase (DCXR) increases the metabolism of Phenanthrene-9,10-dione.	[25]
D-xylulose	DM1ROU7	Investigative	L-xylulose reductase (DCXR) increases the metabolism of D-xylulose.	[25]

24 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 L-xylulose reductase (DCXR).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of L-xylulose reductase (DCXR).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of L-xylulose reductase (DCXR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of L-xylulose reductase (DCXR).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of L-xylulose reductase (DCXR).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of L-xylulose reductase (DCXR).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of L-xylulose reductase (DCXR).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of L-xylulose reductase (DCXR).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of L-xylulose reductase (DCXR).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of L-xylulose reductase (DCXR).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of L-xylulose reductase (DCXR).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of L-xylulose reductase (DCXR).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of L-xylulose reductase (DCXR).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of L-xylulose reductase (DCXR).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of L-xylulose reductase (DCXR).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of L-xylulose reductase (DCXR).	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of L-xylulose reductase (DCXR).	[18]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of L-xylulose reductase (DCXR).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of L-xylulose reductase (DCXR).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of L-xylulose reductase (DCXR).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of L-xylulose reductase (DCXR).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of L-xylulose reductase (DCXR).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of L-xylulose reductase (DCXR).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of L-xylulose reductase (DCXR).	[24]

References

• [1] Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18313-7. doi: 10.1073/pnas.1115888108. Epub 2011 Oct 31.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] 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.
• [16] 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.
• [17] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [18] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [19] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [20] 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.
• [21] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [22] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Diacetyl/l-xylulose reductase mediates chemical redox cycling in lung epithelial cells. Chem Res Toxicol. 2017 Jul 17;30(7):1406-1418.