Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW3520C)

• DOT Name: Apolipoprotein C-III (APOC3)
• Synonyms: Apo-CIII; ApoC-III; Apolipoprotein C3
• Gene Name: APOC3
• Related Disease: Cholesterol-ester transfer protein deficiency
• UniProt ID: APOC3_HUMAN
• PDB ID: 2JQ3
• Pfam ID: PF05778
• Sequence:
  MQPRVLLVVALLALLASARASEAEDASLLSFMQGYMKHATKTAKDALSSVQESQVAQQAR
  GWVTDGFSSLKDYWSTVKDKFSEFWDLDPEVRPTSAVAA
• Function: Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma. Plays a multifaceted role in triglyceride homeostasis. Intracellularly, promotes hepatic very low density lipoprotein 1 (VLDL1) assembly and secretion; extracellularly, attenuates hydrolysis and clearance of triglyceride-rich lipoproteins (TRLs). Impairs the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors. Formed of several curved helices connected via semiflexible hinges, so that it can wrap tightly around the curved micelle surface and easily adapt to the different diameters of its natural binding partners.
• Tissue Specificity: Liver.
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  Chylomicron remodeling (R-HSA-8963901)
  HDL remodeling (R-HSA-8964058)
  Retinoid metabolism and transport (R-HSA-975634)
  Chylomicron assembly (R-HSA-8963888)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholesterol-ester transfer protein deficiency	DISP9UAV	Supportive	Autosomal dominant	[1]

25 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 Apolipoprotein C-III (APOC3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apolipoprotein C-III (APOC3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Apolipoprotein C-III (APOC3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apolipoprotein C-III (APOC3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Apolipoprotein C-III (APOC3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Apolipoprotein C-III (APOC3).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Apolipoprotein C-III (APOC3).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Apolipoprotein C-III (APOC3).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Apolipoprotein C-III (APOC3).	[10]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Apolipoprotein C-III (APOC3).	[11]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Apolipoprotein C-III (APOC3).	[12]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the expression of Apolipoprotein C-III (APOC3).	[13]
Allopurinol	DMLPAOB	Approved	Allopurinol decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Indinavir	DM0T3YH	Approved	Indinavir decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Apolipoprotein C-III (APOC3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Apolipoprotein C-III (APOC3).	[7]
Tetramethylpyrazine	DMC0WNB	Discontinued in Phase 2	Tetramethylpyrazine decreases the expression of Apolipoprotein C-III (APOC3).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Apolipoprotein C-III (APOC3).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Apolipoprotein C-III (APOC3).	[16]
Linalool	DMGZQ5P	Investigative	Linalool decreases the expression of Apolipoprotein C-III (APOC3).	[12]
	DMQNVR8		increases the expression of Apolipoprotein C-III (APOC3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sulindac	DM2QHZU	Approved	Sulindac decreases the secretion of Apolipoprotein C-III (APOC3).	[9]

References

• [1] Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. J Clin Invest. 1991 May;87(5):1724-31. doi: 10.1172/JCI115190.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Toxicogenomics-based discrimination of toxic mechanism in HepG2 human hepatoma cells. Toxicol Sci. 2000 Dec;58(2):399-415.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity. Cell Biol Toxicol. 2021 Apr;37(2):151-175. doi: 10.1007/s10565-020-09537-1. Epub 2020 Jun 14.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [13] The hypolipidemic action of bezafibrate therapy in hypertriglyceridemia is mediated by upregulation of lipoprotein lipase: no effects on VLDL substrate affinity to lipolysis or LDL receptor binding. Atherosclerosis. 2000 Dec;153(2):363-71. doi: 10.1016/s0021-9150(00)00409-3.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Preparation of cardiovascular disease-related genes microarray and its application in exploring ligustrazine-induced changes in endothelial gene expression. Pol J Pharmacol. 2004 Jul-Aug;56(4):427-33.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [17] Small dense LDL and atherogenic lipid profile in HIV-positive adults: influence of lopinavir/ritonavir-containing regimen. AIDS. 2003 Mar 28;17(5):772-4. doi: 10.1097/00002030-200303280-00023.