Details of Drug Off-Target (DOT)

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

DOT Name	Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1)
Synonyms	EC 7.2.1.3; Cytochrome b reductase 1; Duodenal cytochrome b; Ferric-chelate reductase 3
Gene Name	CYBRD1
Related Disease	Colorectal carcinoma ( ) Breast cancer ( ) Breast carcinoma ( ) Chronic kidney disease ( ) Cryohydrocytosis ( ) Hereditary hemochromatosis ( ) Liver cirrhosis ( ) Vitamin A deficiency ( ) Hemochromatosis ( )
UniProt ID	CYBR1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5ZLE; 5ZLG
EC Number	7.2.1.3
Pfam ID	PF03188
Sequence	MAMEGYWRFLALLGSALLVGFLSVIFALVWVLHYREGLGWDGSALEFNWHPVLMVTGFVF IQGIAIIVYRLPWTWKCSKLLMKSIHAGLNAVAAILAIISVVAVFENHNVNNIANMYSLH SWVGLIAVICYLLQLLSGFSVFLLPWAPLSLRAFLMPIHVYSGIVIFGTVIATALMGLTE KLIFSLRDPAYSTFPPEGVFVNTLGLLILVFGALIFWIVTRPQWKRPKEPNSTILHPNGG TEQGARGSMPAYSGNNMDKSDSELNSEVAARKRNLALDEAGQRSTM
Function	Plasma membrane reductase that uses cytoplasmic ascorbate as an electron donor to reduce extracellular Fe(3+) into Fe(2+). Probably functions in dietary iron absorption at the brush border of duodenal enterocytes by producing Fe(2+), the divalent form of iron that can be transported into enterocytes. It is also able to reduce extracellular monodehydro-L-ascorbate and may be involved in extracellular ascorbate regeneration by erythrocytes in blood. May also act as a ferrireductase in airway epithelial cells (Probable). May also function as a cupric transmembrane reductase.
Tissue Specificity	Present in erythrocyte membranes (at protein level). Also expressed in respiratory epithelium.
KEGG Pathway	Mineral absorption (hsa04978 )
Reactome Pathway	Iron uptake and transport (R-HSA-917937 )
BioCyc Pathway	MetaCyc:HS01046-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[3]
Cryohydrocytosis	DISMQHL3	Strong	Biomarker	[4]
Hereditary hemochromatosis	DISVG5MT	Strong	Autosomal recessive	[5]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[6]
Vitamin A deficiency	DISBEPZO	Strong	Biomarker	[7]
Hemochromatosis	DISAPY0H	Limited	Genetic Variation	[4]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[12]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[17]
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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 Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1).	[16]
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References

1	A novel test for gene-ancestry interactions in genome-wide association data.PLoS One. 2012;7(12):e48687. doi: 10.1371/journal.pone.0048687. Epub 2012 Dec 6.
2	DCYTB is a predictor of outcome in breast cancer that functions via iron-independent mechanisms.Breast Cancer Res. 2017 Mar 7;19(1):25. doi: 10.1186/s13058-017-0814-9.
3	Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome.Heart Vessels. 2017 Nov;32(11):1410-1414. doi: 10.1007/s00380-017-1013-4. Epub 2017 Jul 1.
4	Analysis of polymorphism and hepatic expression of duodenal cytochrome b in chronic hepatitis C.J Gastroenterol Hepatol. 2017 Feb;32(2):482-486. doi: 10.1111/jgh.13495.
5	The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
6	Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis.Hepatology. 2004 Feb;39(2):492-9. doi: 10.1002/hep.20038.
7	Vitamin A modulates the expression of genes involved in iron bioavailability.Biol Trace Elem Res. 2012 Oct;149(1):64-70. doi: 10.1007/s12011-012-9397-6. Epub 2012 Apr 14.
8	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
9	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.
10	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.
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	Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
13	Ascorbic acid uptake affects ferritin, Dcytb and Nramp2 expression in Caco-2 cells. Eur J Nutr. 2008 Oct;47(7):401-8. doi: 10.1007/s00394-008-0741-8. Epub 2008 Sep 24.
14	Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
15	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
16	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.
17	From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.