Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT05LF59)

• DOT Name: Copper transport protein ATOX1 (ATOX1)
• Synonyms: Metal transport protein ATX1
• Gene Name: ATOX1
• Related Disease:
  Advanced cancer
  Melanoma
  Prostate cancer
  Prostate carcinoma
  Skin cancer
  Spinocerebellar ataxia
  Spinocerebellar ataxia type 1
  High blood pressure
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Occipital horn syndrome
  Parkinson disease
  Vascular disease
  Partial trisomy of the long arm of chromosome 5
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Inflammation
  Lung neoplasm
  Nasopharyngeal carcinoma
• UniProt ID: ATOX1_HUMAN
• PDB ID: 1FE0; 1FE4; 1FEE; 1TL4; 1TL5; 2K1R; 2LQ9; 3CJK; 3IWL; 3IWX; 4QOT; 4YDX; 4YEA; 5F0W; 5T7L; 7DC1; 7ZC3
• Pfam ID: PF00403
• Sequence:
  MPKHEFSVDMTCGGCAEAVSRVLNKLGGVKYDIDLPNKKVCIESEHSMDTLLATLKKTGK
  TVSYLGLE
• Function: Binds and deliver cytosolic copper to the copper ATPase proteins. May be important in cellular antioxidant defense.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Mineral absorption (hsa04978)
• Reactome Pathway:
  Ion influx/efflux at host-pathogen interface (R-HSA-6803544)
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Skin cancer	DISTM18U	Definitive	Altered Expression	[1]
Spinocerebellar ataxia	DISYMHUK	Definitive	Genetic Variation	[2]
Spinocerebellar ataxia type 1	DISF7BO2	Definitive	Genetic Variation	[2]
High blood pressure	DISY2OHH	Strong	Therapeutic	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Occipital horn syndrome	DISBA58S	Strong	Genetic Variation	[5]
Parkinson disease	DISQVHKL	Strong	Biomarker	[6]
Vascular disease	DISVS67S	Strong	Biomarker	[7]
Partial trisomy of the long arm of chromosome 5	DISFHG81	moderate	Biomarker	[8]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[9]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[9]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[10]
Inflammation	DISJUQ5T	Limited	Biomarker	[9]
Lung neoplasm	DISVARNB	Limited	Biomarker	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[11]

13 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 Copper transport protein ATOX1 (ATOX1).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Copper transport protein ATOX1 (ATOX1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Copper transport protein ATOX1 (ATOX1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Copper transport protein ATOX1 (ATOX1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Copper transport protein ATOX1 (ATOX1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Copper transport protein ATOX1 (ATOX1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Copper transport protein ATOX1 (ATOX1).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Copper transport protein ATOX1 (ATOX1).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Copper transport protein ATOX1 (ATOX1).	[19]
CERC-801	DM3SZ7P	Phase 2	CERC-801 decreases the expression of Copper transport protein ATOX1 (ATOX1).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Copper transport protein ATOX1 (ATOX1).	[22]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Copper transport protein ATOX1 (ATOX1).	[25]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Copper transport protein ATOX1 (ATOX1).	[26]

4 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 increases the methylation of Copper transport protein ATOX1 (ATOX1).	[21]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol increases the oxidation of Copper transport protein ATOX1 (ATOX1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Copper transport protein ATOX1 (ATOX1).	[24]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate increases the methylation of Copper transport protein ATOX1 (ATOX1).	[27]

References

• [1] Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma.Metallomics. 2019 Aug 1;11(8):1430-1440. doi: 10.1039/c9mt00042a. Epub 2019 Jul 18.
• [2] Spinocerebellar ataxia type 1.Handb Clin Neurol. 2012;103:399-421. doi: 10.1016/B978-0-444-51892-7.00025-5.
• [3] Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase.Hypertension. 2012 Aug;60(2):476-86. doi: 10.1161/HYPERTENSIONAHA.111.189571. Epub 2012 Jul 2.
• [4] Knockdown of copper chaperone antioxidant-1 by RNA interference inhibits copper-stimulated proliferation of non-small cell lung carcinoma cells.Oncol Rep. 2013 Jul;30(1):269-75. doi: 10.3892/or.2013.2436. Epub 2013 Apr 29.
• [5] Genomic organization of ATOX1, a human copper chaperone.BMC Genet. 2003 Feb 5;4:4. doi: 10.1186/1471-2156-4-4.
• [6] Neuroprotective effects of Tat-ATOX1 protein against MPP(+)-induced SH-SY5Y cell deaths and in MPTP-induced mouse model of Parkinson's disease.Biochimie. 2019 Jan;156:158-168. doi: 10.1016/j.biochi.2018.10.010. Epub 2018 Oct 21.
• [7] Novel role of copper transport protein antioxidant-1 in neointimal formation after vascular injury.Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):805-13. doi: 10.1161/ATVBAHA.112.300862. Epub 2013 Jan 24.
• [8] Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene.Hum Genet. 2000 Jan;106(1):127-9. doi: 10.1007/s004399900215.
• [9] Novel interaction of antioxidant-1 with TRAF4: role in inflammatory responses in endothelial cells.Am J Physiol Cell Physiol. 2019 Dec 1;317(6):C1161-C1171. doi: 10.1152/ajpcell.00264.2019. Epub 2019 Sep 25.
• [10] Defining the human copper proteome and analysis of its expression variation in cancers.Metallomics. 2017 Feb 22;9(2):112-123. doi: 10.1039/c6mt00202a.
• [11] In vitro cytotoxicity evaluation of thiourea derivatives bearing Salix sp. constituent against HK-1 cell lines.Nat Prod Res. 2020 Jun;34(11):1505-1514. doi: 10.1080/14786419.2018.1517120. Epub 2018 Dec 3.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] 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.
• [19] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [20] Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int. 2013 Apr;62(5):603-9.
• [21] 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.
• [22] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [23] Clioquinol inhibits dopamine--hydroxylase secretion and noradrenaline synthesis by affecting the redox status of ATOX1 and copper transport in human neuroblastoma SH-SY5Y cells. Arch Toxicol. 2021 Jan;95(1):135-148. doi: 10.1007/s00204-020-02894-0. Epub 2020 Oct 9.
• [24] 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.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [26] Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.
• [27] DNA methylation modifies urine biomarker levels in 1,6-hexamethylene diisocyanate exposed workers: a pilot study. Toxicol Lett. 2014 Dec 1;231(2):217-26. doi: 10.1016/j.toxlet.2014.10.024. Epub 2014 Oct 22.