Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT99JKME)

• DOT Name: Aquaporin-8 (AQP8)
• Synonyms: AQP-8
• Gene Name: AQP8
• Related Disease:
  Cervical cancer
  Adult glioblastoma
  Astrocytoma
  Breast cancer
  Breast carcinoma
  Cervical carcinoma
  Cervicitis
  Cholestasis
  Colorectal carcinoma
  Glioblastoma multiforme
  Inflammatory bowel disease
  Irritable bowel syndrome
  Leukemia
  Lung cancer
  Lung carcinoma
  Neoplasm
  Nephrogenic diabetes insipidus
  Polycystic ovarian syndrome
  Prostate carcinoma
  Sweetener
  Synovial sarcoma
  Ulcerative colitis
  Acute otitis media
  leukaemia
  Otitis media
• UniProt ID: AQP8_HUMAN
• Pfam ID: PF00230
• Sequence:
  MSGEIAMCEPEFGNDKAREPSVGGRWRVSWYERFVQPCLVELLGSALFIFIGCLSVIENG
  TDTGLLQPALAHGLALGLVIATLGNISGGHFNPAVSLAAMLIGGLNLVMLLPYWVSQLLG
  GMLGAALAKAVSPEERFWNASGAAFVTVQEQGQVAGALVAEIILTTLLALAVCMGAINEK
  TKGPLAPFSIGFAVTVDILAGGPVSGGCMNPARAFGPAVVANHWNFHWIYWLGPLLAGLL
  VGLLIRCFIGDGKTRLILKAR
• Function: Channel that allows the facilitated permeation of water and uncharged molecules, such as hydrogen peroxide and the neutral form of ammonia (NH3), through cellular membranes such as plasma membrane, inner mitochondrial membrane and endoplasmic reticulum membrane of several tissues. The transport of the ammonia neutral form induces a parallel transport of proton, at alkaline pH when the concentration of ammonia is high. However, it is unclear whether the transport of proton takes place via the aquaporin or via an endogenous pathway. Also, may transport ammonia analogs such as formamide and methylamine, a transport favourited at basic pH due to the increase of unprotonated (neutral) form, which is expected to favor diffusion. Does not transport urea or glycerol. The water transport mechanism is mercury- and copper-sensitive and passive in response to osmotic driving forces. At the canicular plasma membrane, mediates the osmotic transport of water toward the bile canaliculus and facilitates the cAMP-induced bile canalicular water secretion, a process involved in bile formation. In addition, mediates the hydrogen peroxide release from hepatocyte mitochondria that modulates the SREBF2-mediated cholesterol synthesis and facilitates the mitochondrial ammonia uptake which is metabolized into urea, mainly under glucagon stimulation. In B cells, transports the CYBB-generated hydrogen peroxide from the external leaflet of the plasma membrane to the cytosol to promote B cell activation and differentiation for signal amplification. In the small intestine and colon system, mediates water transport through mitochondria and apical membrane of epithelial cells. May play an important role in the adaptive response of proximal tubule cells to acidosis possibly by facilitating the mitochondrial ammonia transport.
• Tissue Specificity: Detected in the sperm midpiece (at protein level) . Expressed only in pancreas and colon.
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway:
  Passive transport by Aquaporins (R-HSA-432047)
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[1]
Cervicitis	DIS4KMW5	Strong	Altered Expression	[4]
Cholestasis	DISDJJWE	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[6]
Irritable bowel syndrome	DIS27206	Strong	Altered Expression	[7]
Leukemia	DISNAKFL	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Nephrogenic diabetes insipidus	DISKNSJK	Strong	Genetic Variation	[10]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[3]
Sweetener	DISDGALM	Strong	Biomarker	[12]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[12]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[13]
Acute otitis media	DISL8D8G	moderate	Altered Expression	[14]
leukaemia	DISS7D1V	moderate	Biomarker	[8]
Otitis media	DISGZDUO	moderate	Altered Expression	[14]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Aquaporin-8 (AQP8) increases the transport of Hydrogen peroxide.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Aquaporin-8 (AQP8).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Aquaporin-8 (AQP8).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Aquaporin-8 (AQP8).	[16]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Aquaporin-8 (AQP8).	[17]
Capecitabine	DMTS85L	Approved	Capecitabine increases the expression of Aquaporin-8 (AQP8).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Aquaporin-8 (AQP8).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Aquaporin-8 (AQP8).	[21]

References

• [1] Increased migration and local invasion potential of SiHa cervical cancer cells expressing Aquaporin 8.Asian Pac J Cancer Prev. 2013;14(3):1825-8. doi: 10.7314/apjcp.2013.14.3.1825.
• [2] Expression of aquaporin8 in human astrocytomas: correlation with pathologic grade.Biochem Biophys Res Commun. 2013 Oct 11;440(1):168-72. doi: 10.1016/j.bbrc.2013.09.057. Epub 2013 Sep 18.
• [3] AQP8 inhibits colorectal cancer growth and metastasis by down-regulating PI3K/AKT signaling and PCDH7 expression.Am J Cancer Res. 2018 Feb 1;8(2):266-279. eCollection 2018.
• [4] Significance and expression of aquaporin 1, 3, 8 in cervical carcinoma in Xinjiang Uygur women of China.Asian Pac J Cancer Prev. 2012;13(5):1971-5. doi: 10.7314/apjcp.2012.13.5.1971.
• [5] Adenoviral transfer of human aquaporin-1 gene to rat liver improves bile flow in estrogen-induced cholestasis.Gene Ther. 2014 Dec;21(12):1058-64. doi: 10.1038/gt.2014.78. Epub 2014 Sep 11.
• [6] Glutathione peroxidase 2 and aquaporin 8 as new markers for colonic inflammation in experimental colitis and inflammatory bowel diseases: an important role for H2O2?.Eur J Gastroenterol Hepatol. 2008 Jun;20(6):555-60. doi: 10.1097/MEG.0b013e3282f45751.
• [7] Aquaporins 1, 3 and 8 expression in irritable bowel syndrome rats' colon via NF-B pathway.Oncotarget. 2017 Jul 18;8(29):47175-47183. doi: 10.18632/oncotarget.17565.
• [8] Sulforaphane Modulates AQP8-Linked Redox Signalling in Leukemia Cells.Oxid Med Cell Longev. 2018 Nov 18;2018:4125297. doi: 10.1155/2018/4125297. eCollection 2018.
• [9] Human colorectal cancer initiation is bidirectional, and cell growth, metabolic genes and transporter genes are early drivers of tumorigenesis.Cancer Lett. 2018 Sep 1;431:213-218. doi: 10.1016/j.canlet.2018.06.005. Epub 2018 Jun 6.
• [10] Structural Basis for Mutations of Human Aquaporins Associated to Genetic Diseases.Int J Mol Sci. 2018 May 25;19(6):1577. doi: 10.3390/ijms19061577.
• [11] AQP8 and AQP9 expression in patients with polycystic ovary syndrome and its association with in vitro fertilization-embryo transfer outcomes.Exp Ther Med. 2019 Jul;18(1):755-760. doi: 10.3892/etm.2019.7592. Epub 2019 May 20.
• [12] Antibodies to aquaporins are frequent in patients with primary Sjgren's syndrome.Rheumatology (Oxford). 2017 Dec 1;56(12):2114-2122. doi: 10.1093/rheumatology/kex328.
• [13] Aquaporin 8 expression is reduced and regulated by microRNAs in patients with ulcerative colitis.Chin Med J (Engl). 2013;126(8):1532-7.
• [14] Expression of aquaporins mRNAs in patients with otitis media.Acta Otolaryngol. 2018 Aug;138(8):701-707. doi: 10.1080/00016489.2018.1447685. Epub 2018 Apr 1.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [18] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Mitochondrial aquaporin-8 knockdown in human hepatoma HepG2 cells causes ROS-induced mitochondrial depolarization and loss of viability. Toxicol Appl Pharmacol. 2012 Oct 15;264(2):246-54. doi: 10.1016/j.taap.2012.08.005. Epub 2012 Aug 15.