Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ66CKX)

• DOT Name: Neutral cholesterol ester hydrolase 1 (NCEH1)
• Synonyms: NCEH; EC 3.1.1.-; Acetylalkylglycerol acetylhydrolase; 2-acetyl MAGE hydrolase; EC 3.1.1.71; Arylacetamide deacetylase-like 1
• Gene Name: NCEH1
• Related Disease:
  Parkinson disease
  Arteriosclerosis
  Atherosclerosis
  Acute myelogenous leukaemia
• UniProt ID: NCEH1_HUMAN
• EC Number: 3.1.1.-; 3.1.1.71
• Pfam ID: PF07859
• Sequence:
  MRSSCVLLTALVALAAYYVYIPLPGSVSDPWKLMLLDATFRGAQQVSNLIHYLGLSHHLL
  ALNFIIVSFGKKSAWSSAQVKVTDTDFDGVEVRVFEGPPKPEEPLKRSVVYIHGGGWALA
  SAKIRYYDELCTAMAEELNAVIVSIEYRLVPKVYFPEQIHDVVRATKYFLKPEVLQKYMV
  DPGRICISGDSAGGNLAAALGQQFTQDASLKNKLKLQALIYPVLQALDFNTPSYQQNVNT
  PILPRYVMVKYWVDYFKGNYDFVQAMIVNNHTSLDVEEAAAVRARLNWTSLLPASFTKNY
  KPVVQTTGNARIVQELPQLLDARSAPLIADQAVLQLLPKTYILTCEHDVLRDDGIMYAKR
  LESAGVEVTLDHFEDGFHGCMIFTSWPTNFSVGIRTRNSYIKWLDQNL
• Function: Hydrolyzes 2-acetyl monoalkylglycerol ether (1-O-alkyl-2-acetyl-sn-glycerol), the penultimate precursor of the pathway for de novo synthesis of platelet-activating factor. May be responsible for the hydrolysis of cholesterol esters (such as cholesteryl (9Z-octadecenoate)) in macrophages. Also involved in organ detoxification by hydrolyzing exogenous organophosphorus compounds. May contribute to cancer pathogenesis by promoting tumor cell migration.
• Tissue Specificity: Expressed in monocyte-derived macrophages. Up-regulated in invasive melanoma and breast carcinoma cell lines.
• KEGG Pathway:
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
  Bile secretion (hsa04976)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway: LDL clearance (R-HSA-8964038)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Neutral cholesterol ester hydrolase 1 (NCEH1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[15]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[20]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon increases the expression of Neutral cholesterol ester hydrolase 1 (NCEH1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neutral cholesterol ester hydrolase 1 (NCEH1).	[18]

References

• [1] NCEH-1 modulates cholesterol metabolism and protects against -synuclein toxicity in a C. elegans model of Parkinson's disease.Hum Mol Genet. 2017 Oct 1;26(19):3823-3836. doi: 10.1093/hmg/ddx269.
• [2] Loss of ACAT1 Attenuates Atherosclerosis Aggravated by Loss of NCEH1 in Bone Marrow-Derived Cells.J Atheroscler Thromb. 2019 Mar 1;26(3):246-259. doi: 10.5551/jat.44040. Epub 2018 Oct 4.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] 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.
• [13] 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.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Chlorpyrifos-induced cell proliferation in human breast cancer cell lines differentially mediated by estrogen and aryl hydrocarbon receptors and KIAA1363 enzyme after 24?h and 14 days exposure. Chemosphere. 2020 Jul;251:126426. doi: 10.1016/j.chemosphere.2020.126426. Epub 2020 Mar 6.