Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3VH359)

• DOT Name: Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2)
• Synonyms: EC 1.17.99.3; 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanoyl-CoA 24-hydroxylase; 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanoyl-CoA oxidase; Trihydroxycoprostanoyl-CoA oxidase; THCA-CoA oxidase; THCCox
• Gene Name: ACOX2
• Related Disease:
  Breast neoplasm
  Cardiovascular disease
  Hepatocellular carcinoma
  Zellweger spectrum disorders
  Congenital bile acid synthesis defect 6
  Breast cancer
  Breast carcinoma
• UniProt ID: ACOX2_HUMAN
• EC Number: 1.17.99.3
• Pfam ID: PF01756 ; PF14749
• Sequence:
  MGSPVHRVSLGDTWSRQMHPDIESERYMQSFDVERLTNILDGGAQNTALRRKVESIIHSY
  PEFSCKDNYFMTQNERYKAAMRRAFHIRLIARRLGWLEDGRELGYAYRALSGDVALNIHR
  VFVRALRSLGSEEQIAKWDPLCKNIQIIATYAQTELGHGTYLQGLETEATYDAATQEFVI
  HSPTLTATKWWPGDLGRSATHALVQAQLICSGARRGMHAFIVPIRSLQDHTPLPGIIIGD
  IGPKMDFDQTDNGFLQLNHVRVPRENMLSRFAQVLPDGTYVKLGTAQSNYLPMVVVRVEL
  LSGEILPILQKACVIAMRYSVIRRQSRLRPSDPEAKVLDYQTQQQKLFPQLAISYAFHFL
  AVSLLEFFQHSYTAILNQDFSFLPELHALSTGMKAMMSEFCTQGAEMCRRACGGHGYSKL
  SGLPSLVTKLSASCTYEGENTVLYLQVARFLVKSYLQTQMSPGSTPQRSLSPSVAYLTAP
  DLARCPAQRAADFLCPELYTTAWAHVAVRLIKDSVQHLQTLTQSGADQHEAWNQTTVIHL
  QAAKVHCYYVTVKGFTEALEKLENEPAIQQVLKRLCDLHAIHGILTNSGDFLHDAFLSGA
  QVDMARTAYLDLLRLIRKDAILLTDAFDFTDQCLNSALGCYDGNVYERLFQWAQKSPTNT
  QENPAYEEYIRPLLQSWRSKL
• Function: Oxidizes the CoA esters of the bile acid intermediates di- and tri-hydroxycholestanoic acids. Capable of oxidizing short as well as long chain 2-methyl branched fatty acids.
• Tissue Specificity: Present in all tissues tested: heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Most abundant in heart, liver and kidney.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Beta-oxidation of pristanoyl-CoA (R-HSA-389887)
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
• BioCyc Pathway: MetaCyc:HS09732-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Zellweger spectrum disorders	DISW52CE	Strong	Biomarker	[4]
Congenital bile acid synthesis defect 6	DIS68TJR	Moderate	Autosomal recessive	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[6]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[6]

18 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 Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[16]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[19]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[20]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[20]
Farnesol	DMV2X1B	Investigative	Farnesol decreases the expression of Peroxisomal acyl-coenzyme A oxidase 2 (ACOX2).	[20]

References

• [1] Expression of an estrogen-regulated variant transcript of the peroxisomal branched chain fatty acid oxidase ACOX2 in breast carcinomas.BMC Cancer. 2015 Jul 17;15:524. doi: 10.1186/s12885-015-1510-8.
• [2] Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease.Eur J Hum Genet. 2011 Jul;19(7):796-800. doi: 10.1038/ejhg.2011.19. Epub 2011 Feb 23.
• [3] Comprehensive gene expression analysis of 5'-end of mRNA identified novel intronic transcripts associated with hepatocellular carcinoma.Genomics. 2010 Apr;95(4):217-23. doi: 10.1016/j.ygeno.2010.01.004. Epub 2010 Jan 21.
• [4] Molecular characterization of the human peroxisomal branched-chain acyl-CoA oxidase: cDNA cloning, chromosomal assignment, tissue distribution, and evidence for the absence of the protein in Zellweger syndrome.Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13748-53. doi: 10.1073/pnas.93.24.13748.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study.Breast Cancer Res. 2017 Dec 11;19(1):131. doi: 10.1186/s13058-017-0914-6.
• [7] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [8] 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.
• [9] 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.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] 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.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [18] 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.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.