Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWRF2NR)

• DOT Name: Dihydropyrimidine dehydrogenase (DPYD)
• Synonyms: DHPDHase; DPD; EC 1.3.1.2; Dihydrothymine dehydrogenase; Dihydrouracil dehydrogenase
• Gene Name: DPYD
• Related Disease: Dihydropyrimidine dehydrogenase deficiency
• UniProt ID: DPYD_HUMAN
• EC Number: 1.3.1.2
• Pfam ID: PF01180 ; PF14691 ; PF14697 ; PF07992
• Sequence:
  MAPVLSKDSADIESILALNPRTQTHATLCSTSAKKLDKKHWKRNPDKNCFNCEKLENNFD
  DIKHTTLGERGALREAMRCLKCADAPCQKSCPTNLDIKSFITSIANKNYYGAAKMIFSDN
  PLGLTCGMVCPTSDLCVGGCNLYATEEGPINIGGLQQFATEVFKAMSIPQIRNPSLPPPE
  KMSEAYSAKIALFGAGPASISCASFLARLGYSDITIFEKQEYVGGLSTSEIPQFRLPYDV
  VNFEIELMKDLGVKIICGKSLSVNEMTLSTLKEKGYKAAFIGIGLPEPNKDAIFQGLTQD
  QGFYTSKDFLPLVAKGSKAGMCACHSPLPSIRGVVIVLGAGDTAFDCATSALRCGARRVF
  IVFRKGFVNIRAVPEEMELAKEEKCEFLPFLSPRKVIVKGGRIVAMQFVRTEQDETGKWN
  EDEDQMVHLKADVVISAFGSVLSDPKVKEALSPIKFNRWGLPEVDPETMQTSEAWVFAGG
  DVVGLANTTVESVNDGKQASWYIHKYVQSQYGASVSAKPELPLFYTPIDLVDISVEMAGL
  KFINPFGLASATPATSTSMIRRAFEAGWGFALTKTFSLDKDIVTNVSPRIIRGTTSGPMY
  GPGQSSFLNIELISEKTAAYWCQSVTELKADFPDNIVIASIMCSYNKNDWTELAKKSEDS
  GADALELNLSCPHGMGERGMGLACGQDPELVRNICRWVRQAVQIPFFAKLTPNVTDIVSI
  ARAAKEGGANGVTATNTVSGLMGLKSDGTPWPAVGIAKRTTYGGVSGTAIRPIALRAVTS
  IARALPGFPILATGGIDSAESGLQFLHSGASVLQVCSAIQNQDFTVIEDYCTGLKALLYL
  KSIEELQDWDGQSPATVSHQKGKPVPRIAELMDKKLPSFGPYLEQRKKIIAENKIRLKEQ
  NVAFSPLKRNCFIPKRPIPTIKDVIGKALQYLGTFGELSNVEQVVAMIDEEMCINCGKCY
  MTCNDSGYQAIQFDPETHLPTITDTCTGCTLCLSVCPIVDCIKMVSRTTPYEPKRGVPLS
  VNPVC
• Function: Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil.
• Tissue Specificity: Found in most tissues with greatest activity found in liver and peripheral blood mononuclear cells.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  beta-Alanine metabolism (hsa00410)
  Pantothe.te and CoA biosynthesis (hsa00770)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Pyrimidine catabolism (R-HSA-73621)
• BioCyc Pathway: MetaCyc:HS06975-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dihydropyrimidine dehydrogenase deficiency	DISF00XA	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Dihydropyrimidine dehydrogenase (DPYD) increases the response to substance of Fluorouracil.	[27]
Tegafur	DM31ZQM	Approved	Dihydropyrimidine dehydrogenase (DPYD) affects the response to substance of Tegafur.	[28]
Flucytosine	DM13VTW	Approved	Dihydropyrimidine dehydrogenase (DPYD) increases the Bone marrow failure ADR of Flucytosine.	[29]

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 Dihydropyrimidine dehydrogenase (DPYD).	[2]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the methylation of Dihydropyrimidine dehydrogenase (DPYD).	[14]

25 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 Dihydropyrimidine dehydrogenase (DPYD).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[13]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[5]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[15]
Docetaxel	DMDI269	Approved	Docetaxel decreases the activity of Dihydropyrimidine dehydrogenase (DPYD).	[16]
Capecitabine	DMTS85L	Approved	Capecitabine increases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[17]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[5]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[24]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[25]
Wogonin	DMGCF51	Investigative	Wogonin decreases the expression of Dihydropyrimidine dehydrogenase (DPYD).	[26]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines. J Gastroenterol. 2006 Feb;41(2):140-50.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [10] Suppression of DPYD expression in RKO cells via DNA methylation in the regulatory region of the DPYD promoter: a potentially important epigenetic mechanism regulating DPYD expression. Biochem Cell Biol. 2007 Jun;85(3):337-46.
• [11] 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.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [14] Aberrant methylation of DPYD promoter, DPYD expression, and cellular sensitivity to 5-fluorouracil in cancer cells. Clin Cancer Res. 2004 Oct 15;10(20):7100-7. doi: 10.1158/1078-0432.CCR-04-0337.
• [15] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [16] Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines. Int J Cancer. 2006 Aug 15;119(4):783-91.
• [17] DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol. 2007 Aug;31(2):413-8.
• [18] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [25] Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. Cancer Sci. 2009 Dec;100(12):2402-10.
• [26] Wogonin potentiates the antitumor effects of low dose 5-fluorouracil against gastric cancer through induction of apoptosis by down-regulation of NF-kappaB and regulation of its metabolism. Toxicol Lett. 2010 Sep 1;197(3):201-10.
• [27] Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity. Eur J Cancer. 1997 Nov;33(13):2258-64. doi: 10.1016/s0959-8049(97)00261-x.
• [28] Dihydropyrimidine dehydrogenases and cytidine-deaminase gene polymorphisms as outcome predictors in resected gastric cancer patients treated with fluoropyrimidine adjuvant chemotherapy. J Surg Oncol. 2008 Aug 1;98(2):130-4.
• [29] 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.