Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA6ICI2)

• DOT Name: Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4)
• Synonyms: DIPP-2B; EC 3.6.1.52; Nucleoside diphosphate-linked moiety X motif 4B; Nudix motif 4B; Nudix hydrolase 4B
• Gene Name: NUDT4
• UniProt ID: NUD4B_HUMAN
• EC Number: 3.6.1.52
• Pfam ID: PF00293
• Sequence:
  MMKFKPNQTRTYDREGFKKRAACLCFRSEQEDEVLLVSSSRYPDQWIVPGGGMEPEEEPG
  GAAVREVYEEAGVKGKLGRLLGIFEQNQDRKHRTYVYVLTVTEILEDWEDSVNIGRKREW
  FKVEDAIKVLQCHKPVHAEYLEKLKLGCSPANGNSTVPSLPDNNALFVTAAQTSGLPSSV
  R
• Function: Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), PP-InsP4 and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction. Also able to catalyze the hydrolysis of dinucleoside oligophosphate Ap6A, but not Ap5A. The major reaction products are ADP and p4a from Ap6A. Also able to hydrolyze 5-phosphoribose 1-diphosphate. Does not play a role in U8 snoRNA decapping activity. Binds U8 snoRNA.

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
Paclitaxel	DMLB81S	Approved	Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4) affects the response to substance of Paclitaxel.	[19]
Topotecan	DMP6G8T	Approved	Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4) affects the response to substance of Topotecan.	[19]
Vinblastine	DM5TVS3	Approved	Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4) affects the response to substance of Vinblastine.	[19]

1 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 Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Diphosphoinositol polyphosphate phosphohydrolase NUDT4B (NUDT4).	[18]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] 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.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.