Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9Y8GA8)

• DOT Name: Carbonic anhydrase-related protein (CA8)
• Synonyms: CARP; Carbonic anhydrase VIII; CA-VIII
• Gene Name: CA8
• Related Disease:
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3
  Adenoma
  Analgesia
  Astrocytoma
  Breast adenocarcinoma
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1
  Colorectal adenoma
  Colorectal carcinoma
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Hypertrophic cardiomyopathy
  Intellectual disability
  Osteoporosis
  Rhabdomyosarcoma
  Stomach cancer
  Cerebellar ataxia
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4
  Gastrointestinal stromal tumour
  Lung adenocarcinoma
  Neoplasm
  Spinocerebellar ataxia type 14
  Stroke
  Cerebellar ataxia, intellectual disability, and dysequilibrium
  Adenocarcinoma
  Bone osteosarcoma
  Carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Non-small-cell lung cancer
  Osteosarcoma
  Parkinson disease
  Renal cell carcinoma
  Spinocerebellar ataxia type 3
• UniProt ID: CAH8_HUMAN
• PDB ID: 2W2J
• Pfam ID: PF00194
• Sequence:
  MADLSFIEDTVAFPEKEEDEEEEEEGVEWGYEEGVEWGLVFPDANGEYQSPINLNSREAR
  YDPSLLDVRLSPNYVVCRDCEVTNDGHTIQVILKSKSVLSGGPLPQGHEFELYEVRFHWG
  RENQRGSEHTVNFKAFPMELHLIHWNSTLFGSIDEAVGKPHGIAIIALFVQIGKEHVGLK
  AVTEILQDIQYKGKSKTIPCFNPNTLLPDPLLRDYWVYEGSLTIPPCSEGVTWILFRYPL
  TISQLQIEEFRRLRTHVKGAELVEGCDGILGDNFRPTQPLSDRVIRAAFQ
• Function: Does not have a carbonic anhydrase catalytic activity.
• KEGG Pathway:
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3	DISYM1WZ	Definitive	Autosomal recessive	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Analgesia	DISK3TVI	Strong	Biomarker	[3]
Astrocytoma	DISL3V18	Strong	Biomarker	[4]
Breast adenocarcinoma	DISMPHJ0	Strong	Altered Expression	[5]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	DISBHBD6	Strong	Biomarker	[6]
Colorectal adenoma	DISTSVHM	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[8]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[9]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[10]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[11]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[12]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[13]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[14]
Cerebellar ataxia	DIS9IRAV	Moderate	Autosomal recessive	[15]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2	DISUFWJU	moderate	Biomarker	[6]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4	DISF9SBX	moderate	Biomarker	[6]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[16]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[17]
Neoplasm	DISZKGEW	moderate	Altered Expression	[4]
Spinocerebellar ataxia type 14	DISMGAYN	moderate	Genetic Variation	[18]
Stroke	DISX6UHX	moderate	Biomarker	[19]
Cerebellar ataxia, intellectual disability, and dysequilibrium	DIS9923V	Supportive	Autosomal recessive	[20]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[17]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[21]
Carcinoma	DISH9F1N	Limited	Altered Expression	[22]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[23]
Colon cancer	DISVC52G	Limited	Biomarker	[7]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[7]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[7]
Lung cancer	DISCM4YA	Limited	Biomarker	[17]
Lung carcinoma	DISTR26C	Limited	Biomarker	[17]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[24]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[17]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[21]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[25]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[23]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[24]

11 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 Carbonic anhydrase-related protein (CA8).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Carbonic anhydrase-related protein (CA8).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Carbonic anhydrase-related protein (CA8).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbonic anhydrase-related protein (CA8).	[29]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Carbonic anhydrase-related protein (CA8).	[30]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Carbonic anhydrase-related protein (CA8).	[31]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Carbonic anhydrase-related protein (CA8).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Carbonic anhydrase-related protein (CA8).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Carbonic anhydrase-related protein (CA8).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Carbonic anhydrase-related protein (CA8).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Carbonic anhydrase-related protein (CA8).	[37]

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 decreases the methylation of Carbonic anhydrase-related protein (CA8).	[33]

References

• [1] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [2] Overexpression of carbonic anhydrase-related protein VIII in human colorectal cancer.J Pathol. 2003 Sep;201(1):37-45. doi: 10.1002/path.1404.
• [3] Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice.Neuroreport. 2017 Dec 13;28(18):1215-1220. doi: 10.1097/WNR.0000000000000872.
• [4] Carbonic anhydrase related protein expression in astrocytomas and oligodendroglial tumors.BMC Cancer. 2018 May 23;18(1):584. doi: 10.1186/s12885-018-4493-4.
• [5] In vitro antiestrogenic effects of aryl methyl sulfone metabolites of polychlorinated biphenyls and 2,2-bis(4-chlorophenyl)-1,1-dichloroethene on 17beta-estradiol-induced gene expression in several bioassay systems.Toxicol Sci. 2002 Oct;69(2):362-72. doi: 10.1093/toxsci/69.2.362.
• [6] Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration.Neurobiol Dis. 2016 Feb;86:86-98. doi: 10.1016/j.nbd.2015.11.008. Epub 2015 Nov 14.
• [7] Carbonic anhydrase-related protein VIII promotes colon cancer cell growth.Mol Carcinog. 2007 Mar;46(3):208-14. doi: 10.1002/mc.20264.
• [8] MLP and CARP are linked to chronic PKC signalling in dilated cardiomyopathy.Nat Commun. 2016 Jun 29;7:12120. doi: 10.1038/ncomms12120.
• [9] Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy. Eur Heart J. 2009 Sep;30(17):2128-36. doi: 10.1093/eurheartj/ehp225. Epub 2009 Jun 12.
• [10] Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy.J Am Coll Cardiol. 2009 Jul 21;54(4):334-42. doi: 10.1016/j.jacc.2008.12.082.
• [11] Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.Hum Mol Genet. 2013 Feb 1;22(3):417-32. doi: 10.1093/hmg/dds438. Epub 2012 Oct 18.
• [12] Nucleotide variations in genes encoding carbonic anhydrase 8 and 10 associated with femoral bone mineral density in Japanese female with osteoporosis.J Bone Miner Metab. 2009;27(2):213-6. doi: 10.1007/s00774-008-0031-9. Epub 2009 Jan 27.
• [13] Carp, a cardiac ankyrin-repeated protein, and its new homologue, Arpp, are differentially expressed in heart, skeletal muscle, and rhabdomyosarcomas.Am J Pathol. 2002 May;160(5):1767-78. doi: 10.1016/S0002-9440(10)61123-6.
• [14] CARP is a potential tumor suppressor in gastric carcinoma and a single-nucleotide polymorphism in CARP gene might increase the risk of gastric carcinoma.PLoS One. 2014 May 28;9(5):e97743. doi: 10.1371/journal.pone.0097743. eCollection 2014.
• [15] 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.
• [16] Overexpression of carbonic anhydrase-related protein XI promotes proliferation and invasion of gastrointestinal stromal tumors.Virchows Arch. 2005 Jul;447(1):66-73. doi: 10.1007/s00428-005-1225-3. Epub 2005 Jun 8.
• [17] Carbonic anhydrase-related protein VIII increases invasiveness of non-small cell lung adenocarcinoma.Virchows Arch. 2006 Jun;448(6):830-7. doi: 10.1007/s00428-006-0199-0. Epub 2006 Apr 12.
• [18] Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development.Curr Neuropharmacol. 2018 Jan 30;16(2):151-159. doi: 10.2174/1570159X15666170529104000.
• [19] Assessment of R18, COG1410, and APP96-110 in Excitotoxicity and Traumatic Brain Injury.Transl Neurosci. 2017 Nov 15;8:147-157. doi: 10.1515/tnsci-2017-0021. eCollection 2017.
• [20] Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII. Am J Med Genet B Neuropsychiatr Genet. 2011 Dec;156B(7):826-34. doi: 10.1002/ajmg.b.31227. Epub 2011 Aug 2.
• [21] Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells.Tumour Biol. 2016 Jun;37(6):7989-8005. doi: 10.1007/s13277-015-4661-y. Epub 2015 Dec 28.
• [22] Expression of carbonic anhydrase-related protein CA-RP VIII in non-small cell lung cancer.Virchows Arch. 2003 Jan;442(1):66-70. doi: 10.1007/s00428-002-0721-y. Epub 2002 Dec 5.
• [23] CA8 promotes RCC proliferation and migration though its expression level is lower in tumor compared to adjacent normal tissue.Biomed Pharmacother. 2020 Jan;121:109578. doi: 10.1016/j.biopha.2019.109578. Epub 2019 Nov 10.
• [24] Protective roles of carbonic anhydrase 8 in Machado-Joseph Disease.J Neurosci Res. 2019 Oct;97(10):1278-1297. doi: 10.1002/jnr.24474. Epub 2019 Jun 3.
• [25] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [26] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [31] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [32] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [33] 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.
• [34] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [35] 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.
• [36] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [37] 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.