Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT55NCTD)

• DOT Name: Serum paraoxonase/arylesterase 2 (PON2)
• Synonyms: PON 2; EC 3.1.1.2; EC 3.1.1.81; Aromatic esterase 2; A-esterase 2; Serum aryldialkylphosphatase 2
• Gene Name: PON2
• Related Disease: Amyotrophic lateral sclerosis
• UniProt ID: PON2_HUMAN
• EC Number: 3.1.1.2; 3.1.1.81
• Pfam ID: PF01731
• Sequence:
  MGRLVAVGLLGIALALLGERLLALRNRLKASREVESVDLPHCHLIKGIEAGSEDIDILPN
  GLAFFSVGLKFPGLHSFAPDKPGGILMMDLKEEKPRARELRISRGFDLASFNPHGISTFI
  DNDDTVYLFVVNHPEFKNTVEIFKFEEAENSLLHLKTVKHELLPSVNDITAVGPAHFYAT
  NDHYFSDPFLKYLETYLNLHWANVVYYSPNEVKVVAEGFDSANGINISPDDKYIYVADIL
  AHEIHVLEKHTNMNLTQLKVLELDTLVDNLSIDPSSGDIWVGCHPNGQKLFVYDPNNPPS
  SEVLRIQNILSEKPTVTTVYANNGSVLQGSSVASVYDGKLLIGTLYHRALYCEL
• Function: Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters. Has antioxidant activity. Is not associated with high density lipoprotein. Prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL, and inhibits the ability of MM-LDL to induce monocyte chemotaxis.
• Tissue Specificity: Widely expressed with highest expression in liver, lung, placenta, testis and heart.
• Reactome Pathway: Synthesis of 5-eicosatetraenoic acids (R-HSA-2142688)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Serum paraoxonase/arylesterase 2 (PON2) affects the response to substance of Arsenic.	[23]
PAI-1	DMY2AEF	Phase 4	Serum paraoxonase/arylesterase 2 (PON2) increases the response to substance of PAI-1.	[26]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Serum paraoxonase/arylesterase 2 (PON2) affects the metabolism of Eicosapentaenoic acid/docosa-hexaenoic acid.	[24]
D-glucose	DMMG2TO	Investigative	Serum paraoxonase/arylesterase 2 (PON2) affects the abundance of D-glucose.	[28]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenylacetic acid	DMQ95GE	Approved	Serum paraoxonase/arylesterase 2 (PON2) increases the hydrolysis of Phenylacetic acid.	[25]
RTR-003632	DM45NHF	Phase 2	Serum paraoxonase/arylesterase 2 (PON2) affects the hydrolysis of RTR-003632.	[27]

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 Serum paraoxonase/arylesterase 2 (PON2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Serum paraoxonase/arylesterase 2 (PON2).	[16]

21 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 Serum paraoxonase/arylesterase 2 (PON2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serum paraoxonase/arylesterase 2 (PON2).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[14]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[18]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[19]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[20]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[21]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Serum paraoxonase/arylesterase 2 (PON2).	[22]

References

• [1] Paraoxonase gene mutations in amyotrophic lateral sclerosis. Ann Neurol. 2010 Jul;68(1):102-7. doi: 10.1002/ana.21993.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Paraoxonase enzyme protects retinal pigment epithelium from chlorpyrifos insult. PLoS One. 2014 Jun 30;9(6):e101380. doi: 10.1371/journal.pone.0101380. eCollection 2014.
• [10] 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.
• [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] 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.
• [13] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [14] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [15] Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy. Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):175-80. doi: 10.1161/01.ATV.0000104011.88939.06. Epub 2003 Oct 30.
• [16] 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.
• [17] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [18] 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.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Chlorpyrifos and parathion regulate oxidative stress differentially through the expression of paraoxonase 2 in human neuroblastoma cell. Neurotoxicology. 2022 Dec;93:60-70. doi: 10.1016/j.neuro.2022.08.016. Epub 2022 Sep 1.
• [21] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [22] Lead inhibits paraoxonase 2 but not paraoxonase 1 activity in human hepatoma HepG2 cells. J Appl Toxicol. 2013 Jul;33(7):631-7. doi: 10.1002/jat.1789. Epub 2012 Jan 23.
• [23] Synergistic effect of polymorphisms of paraoxonase gene cluster and arsenic exposure on electrocardiogram abnormality. Toxicol Appl Pharmacol. 2009 Sep 1;239(2):178-83. doi: 10.1016/j.taap.2008.12.017. Epub 2008 Dec 30.
• [24] Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.
• [25] Paraoxonase gene cluster variations associated with coronary heart disease in Chinese Han women. Chin Med J (Engl). 2005 Jul 20;118(14):1167-74.
• [26] Paraoxonase 2 serves a proapopotic function in mouse and human cells in response to the Pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-homoserine lactone. J Biol Chem. 2015 Mar 13;290(11):7247-58. doi: 10.1074/jbc.M114.620039. Epub 2015 Jan 27.
• [27] Effects of PON polymorphisms and haplotypes on molecular phenotype in Mexican-American mothers and children. Environ Mol Mutagen. 2011 Mar;52(2):105-16. doi: 10.1002/em.20567.
• [28] Detecting the polymorphisms of paraoxonase (PON) cluster in Chinese Han population based on a rapid method. Clin Chim Acta. 2006 Mar;365(1-2):98-103. doi: 10.1016/j.cca.2005.07.034. Epub 2005 Sep 26.