Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNJ9XPL)

• DOT Name: P2X purinoceptor 7 (P2RX7)
• Synonyms: P2X7; ATP receptor; P2Z receptor; Purinergic receptor
• Gene Name: P2RX7
• UniProt ID: P2RX7_HUMAN
• Pfam ID: PF20478 ; PF00864
• Sequence:
  MPACCSCSDVFQYETNKVTRIQSMNYGTIKWFFHVIIFSYVCFALVSDKLYQRKEPVISS
  VHTKVKGIAEVKEEIVENGVKKLVHSVFDTADYTFPLQGNSFFVMTNFLKTEGQEQRLCP
  EYPTRRTLCSSDRGCKKGWMDPQSKGIQTGRCVVYEGNQKTCEVSAWCPIEAVEEAPRPA
  LLNSAENFTVLIKNNIDFPGHNYTTRNILPGLNITCTFHKTQNPQCPIFRLGDIFRETGD
  NFSDVAIQGGIMGIEIYWDCNLDRWFHHCRPKYSFRRLDDKTTNVSLYPGYNFRYAKYYK
  ENNVEKRTLIKVFGIRFDILVFGTGGKFDIIQLVVYIGSTLSYFGLAAVFIDFLIDTYSS
  NCCRSHIYPWCKCCQPCVVNEYYYRKKCESIVEPKPTLKYVSFVDESHIRMVNQQLLGRS
  LQDVKGQEVPRPAMDFTDLSRLPLALHDTPPIPGQPEEIQLLRKEATPRSRDSPVWCQCG
  SCLPSQLPESHRCLEELCCRKKPGACITTSELFRKLVLSRHVLQFLLLYQEPLLALDVDS
  TNSRLRHCAYRCYATWRFGSQDMADFAILPSCCRWRIRKEFPKSEGQYSGFKSPY
• Function: Receptor for ATP that acts as a ligand-gated ion channel. Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells. In the absence of its natural ligand, ATP, functions as a scavenger receptor in the recognition and engulfment of apoptotic cells.
• Tissue Specificity: Widely expressed with highest levels in brain and immune tissues.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Platelet homeostasis (R-HSA-418346)
  The NLRP3 inflammasome (R-HSA-844456)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Elevation of cytosolic Ca2+ levels (R-HSA-139853)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethidium	DMMEQUR	Investigative	P2X purinoceptor 7 (P2RX7) decreases the transport of Ethidium.	[11]

8 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 P2X purinoceptor 7 (P2RX7).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of P2X purinoceptor 7 (P2RX7).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of P2X purinoceptor 7 (P2RX7).	[3]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate increases the activity of P2X purinoceptor 7 (P2RX7).	[4]
Epinephrine	DM3KJBC	Approved	Epinephrine decreases the activity of P2X purinoceptor 7 (P2RX7).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the activity of P2X purinoceptor 7 (P2RX7).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of P2X purinoceptor 7 (P2RX7).	[8]
BzATP	DM37GYA	Investigative	BzATP increases the activity of P2X purinoceptor 7 (P2RX7).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of P2X purinoceptor 7 (P2RX7).	[6]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
AZ11645373	DMDRXCP	Investigative	AZ11645373 affects the binding of P2X purinoceptor 7 (P2RX7).	[10]

References

• [1] 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.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Pharmacological characterization of pannexin-1 currents expressed in mammalian cells. J Pharmacol Exp Ther. 2009 Feb;328(2):409-18. doi: 10.1124/jpet.108.146365. Epub 2008 Nov 20.
• [5] Epidermal growth factor facilitates epinephrine inhibition of P2X7-receptor-mediated pore formation and apoptosis: a novel signaling network. Endocrinology. 2005 Jan;146(1):164-74. doi: 10.1210/en.2004-1026. Epub 2004 Sep 30.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] Bisphenol A, Bisphenol F, and Bisphenol S: The Bad and the Ugly. Where Is the Good?. Life (Basel). 2021 Apr 3;11(4):314. doi: 10.3390/life11040314.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [9] -Nicotinamide Adenine Dinucleotide (-NAD) Inhibits ATP-Dependent IL-1 Release from Human Monocytic Cells. Int J Mol Sci. 2018 Apr 10;19(4):1126. doi: 10.3390/ijms19041126.
• [10] Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket. Mol Pharmacol. 2019 Sep;96(3):355-363. doi: 10.1124/mol.119.116715. Epub 2019 Jul 1.
• [11] A Thr357 to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X7 function and impairs ATP-induced mycobacterial killing by macrophages. J Biol Chem. 2006 Jan 27;281(4):2079-86. doi: 10.1074/jbc.M507816200. Epub 2005 Nov 1.