Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT77XW8)

• DOT Name: Apolipoprotein D (APOD)
• Synonyms: Apo-D; ApoD
• Gene Name: APOD
• Related Disease:
  Central nervous system neoplasm
  Encephalitis
  Multiple sclerosis
  Adenoma
  Advanced cancer
  Alzheimer disease
  Alzheimer disease 3
  Anaplastic astrocytoma
  Androgen insensitivity syndrome
  Autism spectrum disorder
  Bipolar disorder
  Bone osteosarcoma
  Carcinoma
  Colorectal carcinoma
  Glioma
  Helicoid peripapillary chorioretinal degeneration
  Hepatocellular carcinoma
  Hyperinsulinemia
  Hyperthyroidism
  Hypopigmentation of the skin
  Late-onset Parkinson disease
  Neuroblastoma
  Non-insulin dependent diabetes
  Obesity
  Osteosarcoma
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Stroke
  Endometrial carcinoma
  Frontotemporal dementia
  Niemann-Pick disease type C
  Pick disease
  Astrocytoma
  Coronary heart disease
  Glioblastoma multiforme
  Coronary atherosclerosis
  Malignant glioma
  Mental disorder
  Mixed glioma
  Myocardial infarction
  Neoplasm
  Nervous system disease
  Status epilepticus seizure
• UniProt ID: APOD_HUMAN
• PDB ID: 2HZQ; 2HZR
• Pfam ID: PF08212
• Sequence:
  MVMLLLLLSALAGLFGAAEGQAFHLGKCPNPPVQENFDVNKYLGRWYEIEKIPTTFENGR
  CIQANYSLMENGKIKVLNQELRADGTVNQIEGEATPVNLTEPAKLEVKFSWFMPSAPYWI
  LATDYENYALVYSCTCIIQLFHVDFAWILARNPNLPPETVDSLKNILTSNNIDVKKMTVT
  DQVNCPKLS
• Function: APOD occurs in the macromolecular complex with lecithin-cholesterol acyltransferase. It is probably involved in the transport and binding of bilin. Appears to be able to transport a variety of ligands in a number of different contexts.
• Tissue Specificity: Expressed in liver, intestine, pancreas, kidney, placenta, adrenal, spleen, fetal brain tissue and tears.
• Reactome Pathway:
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Transport of fatty acids (R-HSA-804914)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Central nervous system neoplasm	DISFC18W	Definitive	Biomarker	[1]
Encephalitis	DISLD1RL	Definitive	Biomarker	[2]
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[6]
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[7]
Androgen insensitivity syndrome	DISUZBBO	Strong	Altered Expression	[8]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[9]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[10]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[11]
Carcinoma	DISH9F1N	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Helicoid peripapillary chorioretinal degeneration	DISFSS5N	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[14]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[15]
Hyperthyroidism	DISX87ZH	Strong	Altered Expression	[16]
Hypopigmentation of the skin	DIS39YKC	Strong	Genetic Variation	[17]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[18]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[19]
Obesity	DIS47Y1K	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[11]
Parkinson disease	DISQVHKL	Strong	Biomarker	[18]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[20]
Stroke	DISX6UHX	Strong	Genetic Variation	[21]
Endometrial carcinoma	DISXR5CY	moderate	Altered Expression	[22]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[23]
Niemann-Pick disease type C	DIS492ZO	moderate	Altered Expression	[22]
Pick disease	DISP6X50	moderate	Biomarker	[23]
Astrocytoma	DISL3V18	Disputed	Altered Expression	[13]
Coronary heart disease	DIS5OIP1	Disputed	Biomarker	[24]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[13]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[25]
Malignant glioma	DISFXKOV	Limited	Biomarker	[13]
Mental disorder	DIS3J5R8	Limited	Biomarker	[26]
Mixed glioma	DIS64UY3	Limited	Biomarker	[13]
Myocardial infarction	DIS655KI	Limited	Biomarker	[25]
Neoplasm	DISZKGEW	Limited	Altered Expression	[27]
Nervous system disease	DISJ7GGT	Limited	Altered Expression	[28]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[29]

2 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 D (APOD).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Apolipoprotein D (APOD).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Apolipoprotein D (APOD).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Apolipoprotein D (APOD).	[32]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Apolipoprotein D (APOD).	[33]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Apolipoprotein D (APOD).	[34]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Apolipoprotein D (APOD).	[35]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Apolipoprotein D (APOD).	[34]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Apolipoprotein D (APOD).	[36]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Apolipoprotein D (APOD).	[37]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Apolipoprotein D (APOD).	[40]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Apolipoprotein D (APOD).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Apolipoprotein D (APOD).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Apolipoprotein D (APOD).	[36]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Apolipoprotein D (APOD).	[43]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Apolipoprotein D (APOD).	[44]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Apolipoprotein D (APOD).	[31]
propylpyrazoletriol	DMTCP8K	Investigative	propylpyrazoletriol decreases the expression of Apolipoprotein D (APOD).	[45]
diarylpropionitril	DM14X29	Investigative	diarylpropionitril decreases the expression of Apolipoprotein D (APOD).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin A	DMJ2AH4	Approved	Vitamin A affects the binding of Apolipoprotein D (APOD).	[38]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine affects the localization of Apolipoprotein D (APOD).	[39]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug affects the localization of Apolipoprotein D (APOD).	[39]
1-anilinonaphthalene-8-sulfonic acid	DMNGY0E	Investigative	1-anilinonaphthalene-8-sulfonic acid affects the binding of Apolipoprotein D (APOD).	[38]

References

• [1] Differential expression between pilocytic and anaplastic astrocytomas: identification of apolipoprotein D as a marker for low-grade, non-infiltrating primary CNS neoplasms.J Neuropathol Exp Neurol. 2002 Mar;61(3):275-81. doi: 10.1093/jnen/61.3.275.
• [2] Neuroprotective effect of apolipoprotein D against human coronavirus OC43-induced encephalitis in mice.J Neurosci. 2008 Oct 8;28(41):10330-8. doi: 10.1523/JNEUROSCI.2644-08.2008.
• [3] Diagnostic mRNA expression patterns of inflamed, benign, and malignant colorectal biopsy specimen and their correlation with peripheral blood results.Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2835-45. doi: 10.1158/1055-9965.EPI-08-0231.
• [4] Expression and potential role of apolipoprotein D on the death-survival balance of human colorectal cancer cells under oxidative stress conditions.Int J Colorectal Dis. 2013 Jun;28(6):751-66. doi: 10.1007/s00384-012-1616-2. Epub 2013 Jan 8.
• [5] HDX-MS reveals orthosteric and allosteric changes in apolipoprotein-D structural dynamics upon binding of progesterone.Protein Sci. 2019 Feb;28(2):365-374. doi: 10.1002/pro.3534. Epub 2018 Dec 20.
• [6] Genetic variation in apolipoprotein D affects the risk of Alzheimer disease in African-Americans.Am J Med Genet B Neuropsychiatr Genet. 2003 Jan 1;116B(1):98-101. doi: 10.1002/ajmg.b.10798.
• [7] Progression-associated genes in astrocytoma identified by novel microarray gene expression data reanalysis.Methods Mol Biol. 2007;377:203-22. doi: 10.1007/978-1-59745-390-5_13.
• [8] Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome.J Mol Med (Berl). 2009 Jun;87(6):623-32. doi: 10.1007/s00109-009-0462-3. Epub 2009 Mar 30.
• [9] Serum glycopattern and Maackia amurensis lectin-II binding glycoproteins in autism spectrum disorder.Sci Rep. 2017 May 9;7:46041. doi: 10.1038/srep46041.
• [10] Apolipoprotein D modulates arachidonic acid signaling in cultured cells: implications for psychiatric disorders.Prostaglandins Leukot Essent Fatty Acids. 2003 Dec;69(6):421-7. doi: 10.1016/j.plefa.2003.08.014.
• [11] p53 family members regulate the expression of the apolipoprotein D gene.J Biol Chem. 2009 Jan 9;284(2):872-83. doi: 10.1074/jbc.M807185200. Epub 2008 Nov 11.
• [12] Identification of apolipoprotein D as a novel inhibitor of osteopontin-induced neoplastic transformation.Int J Oncol. 2006 Dec;29(6):1591-9.
• [13] Identification of novel genes associated with astrocytoma progression using suppression subtractive hybridization and real-time reverse transcription-polymerase chain reaction.Int J Cancer. 2006 Nov 15;119(10):2330-8. doi: 10.1002/ijc.22108.
• [14] Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma.Int J Cancer. 2005 Aug 10;116(1):105-9. doi: 10.1002/ijc.20986.
• [15] High ApoD protein level in the round ligament fat depot of severely obese women is associated with an improved inflammatory profile.Endocrine. 2018 Aug;61(2):248-257. doi: 10.1007/s12020-018-1621-5. Epub 2018 Jun 4.
• [16] Hippocampal Up-Regulation of Apolipoprotein D in a Rat Model of Maternal Hypo- and Hyperthyroidism: Implication of Oxidative Stress.Neurochem Res. 2019 Sep;44(9):2190-2201. doi: 10.1007/s11064-019-02859-5. Epub 2019 Aug 14.
• [17] Pre-control relationship of onchocercal skin disease with onchocercal infection in Guinea Savanna, Northern Nigeria.PLoS Negl Trop Dis. 2017 Mar 29;11(3):e0005489. doi: 10.1371/journal.pntd.0005489. eCollection 2017 Mar.
• [18] Apolipoprotein D Concentration in Human Plasma during Aging and in Parkinson's Disease: A Cross-Sectional Study.Parkinsons Dis. 2018 Mar 26;2018:3751516. doi: 10.1155/2018/3751516. eCollection 2018.
• [19] Apolipoprotein-D polymorphism: a genetic marker for obesity and hyperinsulinemia.J Clin Endocrinol Metab. 1994 Aug;79(2):568-70. doi: 10.1210/jcem.79.2.7913935.
• [20] Apolipoprotein-D: a novel cellular marker for HGPIN and prostate cancer.Prostate. 2004 Feb 1;58(2):103-8. doi: 10.1002/pros.10343.
• [21] Variations in apolipoprotein D and sigma non-opioid intracellular receptor 1 genes with relation to risk, severity and outcome of ischemic stroke.BMC Neurol. 2014 Sep 28;14:191. doi: 10.1186/s12883-014-0191-2.
• [22] Apolipoprotein D expression in retinoblastoma.Ophthalmic Res. 2003 Mar-Apr;35(2):111-6. doi: 10.1159/000069130.
• [23] Apolipoprotein D Upregulation in Alzheimer's Disease but Not Frontotemporal Dementia.J Mol Neurosci. 2019 Jan;67(1):125-132. doi: 10.1007/s12031-018-1217-9. Epub 2018 Nov 22.
• [24] Differential urinary proteins to diagnose coronary heart disease based on iTRAQ quantitative proteomics.Anal Bioanal Chem. 2019 Apr;411(11):2273-2282. doi: 10.1007/s00216-019-01668-7. Epub 2019 Feb 26.
• [25] Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease.Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17023-8. doi: 10.1073/pnas.1315986110. Epub 2013 Sep 30.
• [26] From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders.Curr Mol Med. 2003 Aug;3(5):408-18. doi: 10.2174/1566524033479681.
• [27] Apolipoprotein D expression does not predict breast cancer recurrence among tamoxifen-treated patients.PLoS One. 2017 Mar 16;12(3):e0171453. doi: 10.1371/journal.pone.0171453. eCollection 2017.
• [28] Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain.Neurobiol Aging. 2014 Jul;35(7):1632-42. doi: 10.1016/j.neurobiolaging.2014.01.148. Epub 2014 Feb 5.
• [29] Hippocampal alterations of apolipoprotein E and D mRNA levels in vivo and in vitro following kainate excitotoxicity.Epilepsy Res. 1999 Jun;35(2):135-46. doi: 10.1016/s0920-1211(99)00003-0.
• [30] 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.
• [31] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [32] 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.
• [33] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [34] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [35] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [38] Comparative ligand-binding analysis of ten human lipocalins. Biochim Biophys Acta. 2006 Feb;1764(2):161-73. doi: 10.1016/j.bbapap.2005.12.006. Epub 2006 Jan 6.
• [39] Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress. PLoS Genet. 2017 Feb 9;13(2):e1006603. doi: 10.1371/journal.pgen.1006603. eCollection 2017 Feb.
• [40] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [41] 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.
• [42] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [43] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [44] Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems. Glia. 2011 Oct;59(10):1551-66. doi: 10.1002/glia.21200. Epub 2011 Jun 17.
• [45] Morphologic effects of estrogen stimulation on 3D MCF-7 microtissues. Toxicol Lett. 2016 Apr 25;248:1-8.