Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80W9TA)

• DOT Name: Serum paraoxonase/lactonase 3 (PON3)
• Synonyms: EC 3.1.1.2; EC 3.1.1.81; EC 3.1.8.1
• Gene Name: PON3
• Related Disease: Amyotrophic lateral sclerosis
• UniProt ID: PON3_HUMAN
• EC Number: 3.1.1.2; 3.1.1.81; 3.1.8.1
• Pfam ID: PF01731
• Sequence:
  MGKLVALVLLGVGLSLVGEMFLAFRERVNASREVEPVEPENCHLIEELESGSEDIDILPS
  GLAFISSGLKYPGMPNFAPDEPGKIFLMDLNEQNPRAQALEISGGFDKELFNPHGISIFI
  DKDNTVYLYVVNHPHMKSTVEIFKFEEQQRSLVYLKTIKHELLKSVNDIVVLGPEQFYAT
  RDHYFTNSLLSFFEMILDLRWTYVLFYSPREVKVVAKGFCSANGITVSADQKYVYVADVA
  AKNIHIMEKHDNWDLTQLKVIQLGTLVDNLTVDPATGDILAGCHPNPMKLLNYNPEDPPG
  SEVLRIQNVLSEKPRVSTVYANNGSVLQGTSVASVYHGKILIGTVFHKTLYCEL
• Function: Has low activity towards the organophosphate paraxon and aromatic carboxylic acid esters. Rapidly hydrolyzes lactones such as statin prodrugs (e.g. lovastatin). Hydrolyzes aromatic lactones and 5- or 6-member ring lactones with aliphatic substituents but not simple lactones or those with polar substituents.
• Reactome Pathway:
  Atorvastatin ADME (R-HSA-9754706)
  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 Biotransformations of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lovastatin	DM9OZWQ	Approved	Serum paraoxonase/lactonase 3 (PON3) increases the hydrolysis of Lovastatin.	[9]
Spironolactone	DM2AQ5N	Approved	Serum paraoxonase/lactonase 3 (PON3) increases the hydrolysis of Spironolactone.	[9]
Phenylacetic acid	DMQ95GE	Approved	Serum paraoxonase/lactonase 3 (PON3) increases the hydrolysis of Phenylacetic acid.	[10]
RTR-003632	DM45NHF	Phase 2	Serum paraoxonase/lactonase 3 (PON3) affects the hydrolysis of RTR-003632.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Serum paraoxonase/lactonase 3 (PON3) affects the metabolism of Eicosapentaenoic acid/docosa-hexaenoic acid.	[9]

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 Serum paraoxonase/lactonase 3 (PON3).	[2]

6 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/lactonase 3 (PON3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serum paraoxonase/lactonase 3 (PON3).	[4]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Serum paraoxonase/lactonase 3 (PON3).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Serum paraoxonase/lactonase 3 (PON3).	[6]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Serum paraoxonase/lactonase 3 (PON3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serum paraoxonase/lactonase 3 (PON3).	[8]

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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] 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.
• [7] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [8] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [9] 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.
• [10] Cloning, high level expression of human paraoxonase-3 in Sf9 cells and pharmacological characterization of its product. Biochem Pharmacol. 2005 Oct 1;70(7):1019-25. doi: 10.1016/j.bcp.2005.07.004.
• [11] 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.