Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX5MYX9)

• DOT Name: Aquaporin-1 (AQP1)
• Synonyms: AQP-1; Aquaporin-CHIP; Urine water channel; Water channel protein for red blood cells and kidney proximal tubule
• Gene Name: AQP1
• Related Disease: Pulmonary arterial hypertension
• UniProt ID: AQP1_HUMAN
• PDB ID: 1FQY; 1H6I; 1IH5; 4CSK; 6POJ; 7UZE; 8CT2; 8CTE
• Pfam ID: PF00230
• Sequence:
  MASEFKKKLFWRAVVAEFLATTLFVFISIGSALGFKYPVGNNQTAVQDNVKVSLAFGLSI
  ATLAQSVGHISGAHLNPAVTLGLLLSCQISIFRALMYIIAQCVGAIVATAILSGITSSLT
  GNSLGRNDLADGVNSGQGLGIEIIGTLQLVLCVLATTDRRRRDLGGSAPLAIGLSVALGH
  LLAIDYTGCGINPARSFGSAVITHNFSNHWIFWVGPFIGGALAVLIYDFILAPRSSDLTD
  RVKVWTSGQVEEYDLDADDINSRVEMKPK
• Function: Forms a water-specific channel that provides the plasma membranes of red cells and kidney proximal tubules with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.
• Tissue Specificity: Detected in erythrocytes (at protein level). Expressed in a number of tissues including erythrocytes, renal tubules, retinal pigment epithelium, heart, lung, skeletal muscle, kidney and pancreas. Weakly expressed in brain, placenta and liver.
• KEGG Pathway:
  Renin secretion (hsa04924)
  Proximal tubule bicarbo.te reclamation (hsa04964)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Erythrocytes take up oxygen and release carbon dioxide (R-HSA-1247673)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Passive transport by Aquaporins (R-HSA-432047)
  Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Aquaporin-1 (AQP1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aquaporin-1 (AQP1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aquaporin-1 (AQP1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Aquaporin-1 (AQP1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Aquaporin-1 (AQP1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Aquaporin-1 (AQP1).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Aquaporin-1 (AQP1).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Aquaporin-1 (AQP1).	[11]
Acetazolamide	DM1AF5U	Approved	Acetazolamide decreases the expression of Aquaporin-1 (AQP1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Aquaporin-1 (AQP1).	[13]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Aquaporin-1 (AQP1).	[13]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Aquaporin-1 (AQP1).	[14]
Guaiacol	DMN4E7T	Phase 3	Guaiacol increases the expression of Aquaporin-1 (AQP1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Aquaporin-1 (AQP1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Aquaporin-1 (AQP1).	[15]
Puerarin	DMJIMXH	Phase 2	Puerarin increases the expression of Aquaporin-1 (AQP1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Aquaporin-1 (AQP1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Aquaporin-1 (AQP1).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Aquaporin-1 (AQP1).	[20]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Aquaporin-1 (AQP1).	[21]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Aquaporin-1 (AQP1).	[13]
pCMPS	DMGIS5Q	Investigative	pCMPS decreases the activity of Aquaporin-1 (AQP1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Aquaporin-1 (AQP1).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Aquaporin-1 (AQP1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Aquaporin-1 (AQP1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aquaporin-1 (AQP1).	[19]

References

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• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [4] 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.
• [5] 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.
• [6] Inorganic arsenic as an endocrine disruptor: modulation of the glucocorticoid receptor pathway in placental cells via CpG methylation. Chem Res Toxicol. 2019 Mar 18;32(3):493-499.
• [7] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [8] 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.
• [9] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [10] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [11] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [12] [Effect of inhibiting aquaporin-1 on proliferation and apoptosis of the Hep-2 cell]. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2006 Nov;20(21):988-91.
• [13] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [14] Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res. 2009 May;77(3):314-26.
• [15] 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.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] 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.
• [19] 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.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [21] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [22] Mercurial sensitivity of aquaporin 1 endofacial loop B residues. Protein Sci. 2001 Aug;10(8):1627-34. doi: 10.1110/ps.5901.