Details of Drug Off-Target (DOT)

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

• DOT Name: Apolipoprotein C-II (APOC2)
• Synonyms: Apo-CII; ApoC-II; Apolipoprotein C2
• Gene Name: APOC2
• Related Disease:
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Myocardial infarction
  Acute megakaryoblastic leukemia
  Amyloidosis
  Arteriosclerosis
  Atherosclerosis
  Cardiovascular disease
  Dysbetalipoproteinemia
  Familial apolipoprotein C-II deficiency
  Familial lipoprotein lipase deficiency
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hyperlipoproteinemia
  Insulinoma
  Multiple sclerosis
  Neoplasm
  Retinoblastoma
  Xanthomatosis
  Pancreatitis
  Hypobetalipoproteinemia
  Chronic pancreatitis
  Glioma
  Hyperlipidemia
  Myotonic dystrophy
  Myotonic dystrophy type 1
• UniProt ID: APOC2_HUMAN
• PDB ID: 1BY6; 1I5J; 1O8T; 1SOH
• Pfam ID: PF05355
• Sequence:
  MGTRLLPALFLVLLVLGFEVQGTQQPQQDEMPSPTFLTQVKESLSSYWESAKTAAQNLYE
  KTYLPAVDEKLRDLYSKSTAAMSTYTGIFTDQVLSVLKGEE
• Function: Component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) in plasma. Plays an important role in lipoprotein metabolism as an activator of lipoprotein lipase. Both proapolipoprotein C-II and apolipoprotein C-II can activate lipoprotein lipase. In normolipidemic individuals, it is mainly distributed in the HDL, whereas in hypertriglyceridemic individuals, predominantly found in the VLDL and LDL.
• Tissue Specificity: Liver and intestine.
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Chylomicron remodeling (R-HSA-8963901)
  HDL remodeling (R-HSA-8964058)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Retinoid metabolism and transport (R-HSA-975634)
  Chylomicron assembly (R-HSA-8963888)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypercholesterolemia	DISC06IX	Definitive	Altered Expression	[1]
Hypercholesterolemia, familial, 1	DISU411W	Definitive	Altered Expression	[1]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[2]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[5]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[5]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[6]
Dysbetalipoproteinemia	DISNRSNM	Strong	Genetic Variation	[7]
Familial apolipoprotein C-II deficiency	DISGQOKX	Strong	Autosomal recessive	[8]
Familial lipoprotein lipase deficiency	DIS0M7NJ	Strong	Genetic Variation	[9]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Hyperlipoproteinemia	DISVBLBO	Strong	Genetic Variation	[12]
Insulinoma	DISIU1JS	Strong	Altered Expression	[13]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[15]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[15]
Xanthomatosis	DIS6KXVS	Strong	Biomarker	[16]
Pancreatitis	DIS0IJEF	moderate	Genetic Variation	[17]
Hypobetalipoproteinemia	DIS0TPI3	Disputed	Biomarker	[18]
Chronic pancreatitis	DISBUOMJ	Limited	Genetic Variation	[19]
Glioma	DIS5RPEH	Limited	Biomarker	[20]
Hyperlipidemia	DIS61J3S	Limited	Genetic Variation	[21]
Myotonic dystrophy	DISNBEMX	Limited	Biomarker	[22]
Myotonic dystrophy type 1	DISJC0OX	Limited	Genetic Variation	[23]

7 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-II (APOC2).	[24]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apolipoprotein C-II (APOC2).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apolipoprotein C-II (APOC2).	[26]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Apolipoprotein C-II (APOC2).	[27]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Apolipoprotein C-II (APOC2).	[28]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Apolipoprotein C-II (APOC2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Apolipoprotein C-II (APOC2).	[31]

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 affects the methylation of Apolipoprotein C-II (APOC2).	[30]

References

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• [2] Apolipoprotein gene polymorphisms and plasma levels in healthy Tunisians and patients with coronary artery disease.Lipids Health Dis. 2008 Nov 17;7:46. doi: 10.1186/1476-511X-7-46.
• [3] Integrated differential transcriptome maps of Acute Megakaryoblastic Leukemia (AMKL) in children with or without Down Syndrome (DS).BMC Med Genomics. 2014 Dec 5;7:63. doi: 10.1186/s12920-014-0063-z.
• [4] Novel Type of Renal Amyloidosis Derived from Apolipoprotein-CII.J Am Soc Nephrol. 2017 Feb;28(2):439-445. doi: 10.1681/ASN.2015111228. Epub 2016 Jun 13.
• [5] Expression of the apolipoprotein C-II gene during myelomonocytic differentiation of human leukemic cells.J Leukoc Biol. 2001 Apr;69(4):645-50.
• [6] Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils.FEBS J. 2018 Aug;285(15):2799-2812. doi: 10.1111/febs.14517. Epub 2018 Jun 9.
• [7] Apolipoprotein gene cluster on chromosome 19. Definite localization of the APOC2 gene and the polymorphic Hpa I site associated with type III hyperlipoproteinemia.Hum Genet. 1988 Jan;78(1):90-3. doi: 10.1007/BF00291243.
• [8] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [9] Severe hyperchylomicronemia in two infants with novel APOC2 gene mutation.J Pediatr Endocrinol Metab. 2018 Nov 27;31(11):1289-1293. doi: 10.1515/jpem-2018-0280.
• [10] Amphipathic -helices in apolipoproteins are crucial to the formation of infectious hepatitis C virus particles.PLoS Pathog. 2014 Dec 11;10(12):e1004534. doi: 10.1371/journal.ppat.1004534. eCollection 2014 Dec.
• [11] Apolipoprotein C-II mRNA levels in primate liver. Induction by estrogen in the human hepatocarcinoma cell line, HepG2.J Biol Chem. 1985 Feb 10;260(3):1676-81.
• [12] The apolipoprotein C-II variant apoC-IILys19-->Thr is not associated with dyslipidemia in an affected kindred.Clin Genet. 1994 Jun;45(6):292-7. doi: 10.1111/j.1399-0004.1994.tb04033.x.
• [13] HNF4alpha and HNF1alpha dysfunction as a molecular rational for cyclosporine induced posttransplantation diabetes mellitus.PLoS One. 2009;4(3):e4662. doi: 10.1371/journal.pone.0004662. Epub 2009 Mar 2.
• [14] Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes.PLoS One. 2018 Aug 16;13(8):e0202530. doi: 10.1371/journal.pone.0202530. eCollection 2018.
• [15] Hypermethylation of adenomatosis polyposis coli-2 and its tumor suppressor role in retinoblastoma.Curr Eye Res. 2015 Jul;40(7):719-28. doi: 10.3109/02713683.2014.954673. Epub 2014 Sep 10.
• [16] A variant primary structure of apolipoprotein C-II in individuals of African descent.J Clin Invest. 1986 Feb;77(2):595-601. doi: 10.1172/JCI112342.
• [17] Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence.J Clin Lipidol. 2019 Jan-Feb;13(1):89-99. doi: 10.1016/j.jacl.2018.09.007. Epub 2018 Sep 18.
• [18] Apolipoprotein C-II and C-III metabolism in a kindred of familial hypobetalipoproteinemia.Metabolism. 1991 Jan;40(1):45-50. doi: 10.1016/0026-0495(91)90191-x.
• [19] A Novel APOC2 Missense Mutation Causing Apolipoprotein C-II Deficiency With Severe Triglyceridemia and Pancreatitis.J Clin Endocrinol Metab. 2017 May 1;102(5):1454-1457. doi: 10.1210/jc.2016-3903.
• [20] The putative glioma tumor suppressor gene on chromosome 19q maps between APOC2 and HRC.Cancer Res. 1994 Sep 1;54(17):4760-3.
• [21] Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia.Dis Model Mech. 2015 Aug 1;8(8):989-98. doi: 10.1242/dmm.019836. Epub 2015 Jun 4.
• [22] Preimplantation genetic diagnosis for myotonic dystrophy type 1: detection of crossover between the gene and the linked marker APOC2.Prenat Diagn. 2007 Feb;27(2):111-6. doi: 10.1002/pd.1611.
• [23] Prenatal diagnosis for dystrophia myotonica using the polymerase chain reaction.Prenat Diagn. 1991 Jul;11(7):467-70. doi: 10.1002/pd.1970110710.
• [24] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [25] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] 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.
• [28] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [29] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [30] 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.
• [31] 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.