Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT466POQ)

• DOT Name: Apolipoprotein A-IV (APOA4)
• Synonyms: Apo-AIV; ApoA-IV; Apolipoprotein A4
• Gene Name: APOA4
• UniProt ID: APOA4_HUMAN
• PDB ID: 3S84
• Pfam ID: PF01442
• Sequence:
  MFLKAVVLTLALVAVAGARAEVSADQVATVMWDYFSQLSNNAKEAVEHLQKSELTQQLNA
  LFQDKLGEVNTYAGDLQKKLVPFATELHERLAKDSEKLKEEIGKELEELRARLLPHANEV
  SQKIGDNLRELQQRLEPYADQLRTQVSTQAEQLRRQLTPYAQRMERVLRENADSLQASLR
  PHADELKAKIDQNVEELKGRLTPYADEFKVKIDQTVEELRRSLAPYAQDTQEKLNHQLEG
  LTFQMKKNAEELKARISASAEELRQRLAPLAEDVRGNLRGNTEGLQKSLAELGGHLDQQV
  EEFRRRVEPYGENFNKALVQQMEQLRQKLGPHAGDVEGHLSFLEKDLRDKVNSFFSTFKE
  KESQDKTLSLPELEQQQEQQQEQQQEQVQMLAPLES
• Function: May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.
• Tissue Specificity: Synthesized primarily in the intestine and secreted in plasma.
• KEGG Pathway:
  Fat digestion and absorption (hsa04975)
  Vitamin digestion and absorption (hsa04977)
  Cholesterol metabolism (hsa04979)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Chylomicron remodeling (R-HSA-8963901)
  Retinoid metabolism and transport (R-HSA-975634)
  Amyloid fiber formation (R-HSA-977225)
  Chylomicron assembly (R-HSA-8963888)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Apolipoprotein A-IV (APOA4).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Apolipoprotein A-IV (APOA4).	[6]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Apolipoprotein A-IV (APOA4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Apolipoprotein A-IV (APOA4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Apolipoprotein A-IV (APOA4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Apolipoprotein A-IV (APOA4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apolipoprotein A-IV (APOA4).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Apolipoprotein A-IV (APOA4).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Apolipoprotein A-IV (APOA4).	[8]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Apolipoprotein A-IV (APOA4).	[9]
Fructose	DM43AN2	Approved	Fructose increases the expression of Apolipoprotein A-IV (APOA4).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Apolipoprotein A-IV (APOA4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Apolipoprotein A-IV (APOA4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Apolipoprotein A-IV (APOA4).	[14]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Apolipoprotein A-IV (APOA4).	[15]

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] 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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] 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.
• [8] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [9] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [10] Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
• [11] Fructose intake increases hyperlipidemia and modifies apolipoprotein expression in apolipoprotein AI-CIII-AIV transgenic mice. J Nutr. 2002 May;132(5):918-23. doi: 10.1093/jn/132.5.918.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Bisphenol a induces steatosis in HepaRG cells using a model of perinatal exposure. Environ Toxicol. 2017 Mar;32(3):1024-1036. doi: 10.1002/tox.22301. Epub 2016 Jun 20.
• [15] A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: application to acetaminophen. Toxicol Appl Pharmacol. 2016 Feb 1;292:40-55.