Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEGBTE1)

• DOT Name: P2X purinoceptor 4 (P2RX4)
• Synonyms: P2X4; ATP receptor; Purinergic receptor
• Gene Name: P2RX4
• UniProt ID: P2RX4_HUMAN
• Pfam ID: PF00864
• Sequence:
  MAGCCAALAAFLFEYDTPRIVLIRSRKVGLMNRAVQLLILAYVIGWVFVWEKGYQETDSV
  VSSVTTKVKGVAVTNTSKLGFRIWDVADYVIPAQEENSLFVMTNVILTMNQTQGLCPEIP
  DATTVCKSDASCTAGSAGTHSNGVSTGRCVAFNGSVKTCEVAAWCPVEDDTHVPQPAFLK
  AAENFTLLVKNNIWYPKFNFSKRNILPNITTTYLKSCIYDAKTDPFCPIFRLGKIVENAG
  HSFQDMAVEGGIMGIQVNWDCNLDRAASLCLPRYSFRRLDTRDVEHNVSPGYNFRFAKYY
  RDLAGNEQRTLIKAYGIRFDIIVFGKAGKFDIIPTMINIGSGLALLGMATVLCDIIVLYC
  MKKRLYYREKKYKYVEDYEQGLASELDQ
• Function: ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium. Activated by extracellularly released ATP, it plays multiple role in immunity and central nervous system physiology. Plays a key role in initial steps of T-cell activation and Ca(2+) microdomain formation. Participates also in basal T-cell activity without TCR/CD3 stimulation. Promotes the differentiation and activation of Th17 cells via expression of retinoic acid-related orphan receptor C/RORC. Upon activation, drives microglia motility via the PI3K/Akt pathway. Could also function as an ATP-gated cation channel of lysosomal membranes.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Platelet homeostasis (R-HSA-418346)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Elevation of cytosolic Ca2+ levels (R-HSA-139853)

Molecular Interaction Atlas (MIA) of This DOT

14 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 P2X purinoceptor 4 (P2RX4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of P2X purinoceptor 4 (P2RX4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of P2X purinoceptor 4 (P2RX4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of P2X purinoceptor 4 (P2RX4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of P2X purinoceptor 4 (P2RX4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of P2X purinoceptor 4 (P2RX4).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of P2X purinoceptor 4 (P2RX4).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of P2X purinoceptor 4 (P2RX4).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of P2X purinoceptor 4 (P2RX4).	[10]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate increases the activity of P2X purinoceptor 4 (P2RX4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of P2X purinoceptor 4 (P2RX4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of P2X purinoceptor 4 (P2RX4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of P2X purinoceptor 4 (P2RX4).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of P2X purinoceptor 4 (P2RX4).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of P2X purinoceptor 4 (P2RX4).	[7]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [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] 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.
• [5] 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.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [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] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [11] Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists. Biochem Pharmacol. 2016 Sep 15;116:130-9. doi: 10.1016/j.bcp.2016.07.020. Epub 2016 Jul 29.
• [12] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [13] 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.
• [14] 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.
• [15] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.