Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLGH5ZY)

• DOT Name: Aquaporin-9 (AQP9)
• Synonyms: AQP-9; Aquaglyceroporin-9; Small solute channel 1
• Gene Name: AQP9
• UniProt ID: AQP9_HUMAN
• Pfam ID: PF00230
• Sequence:
  MQPEGAEKGKSFKQRLVLKSSLAKETLSEFLGTFILIVLGCGCVAQAILSRGRFGGVITI
  NVGFSMAVAMAIYVAGGVSGGHINPAVSLAMCLFGRMKWFKLPFYVGAQFLGAFVGAATV
  FGIYYDGLMSFAGGKLLIVGENATAHIFATYPAPYLSLANAFADQVVATMILLIIVFAIF
  DSRNLGAPRGLEPIAIGLLIIVIASSLGLNSGCAMNPARDLSPRLFTALAGWGFEVFRAG
  NNFWWIPVVGPLVGAVIGGLIYVLVIEIHHPEPDSVFKTEQSEDKPEKYELSVIM
• Function: Forms a water channel with a broad specificity. Also permeable glycerol and urea. Mediates passage of a wide variety of small, non-charged solutes including carbamides, polyols, purines, and pyrimidines.
• Tissue Specificity: Highly expressed in peripheral leukocytes. Also expressed in liver, lung, and spleen.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Passive transport by Aquaporins (R-HSA-432047)
  Transport of glycerol from adipocytes to the liver by Aquaporins (R-HSA-432030)
• BioCyc Pathway: MetaCyc:ENSG00000103569-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Aquaporin-9 (AQP9) increases the import of Arsenic trioxide.	[2]
Urea	DMUK75B	Approved	Aquaporin-9 (AQP9) increases the transport of Urea.	[14]
Selenious acid	DMB7GPA	Investigative	Aquaporin-9 (AQP9) increases the uptake of Selenious acid.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aquaporin-9 (AQP9).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Aquaporin-9 (AQP9).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aquaporin-9 (AQP9).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Aquaporin-9 (AQP9).	[4]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Aquaporin-9 (AQP9).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Aquaporin-9 (AQP9).	[6]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Aquaporin-9 (AQP9).	[7]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Aquaporin-9 (AQP9).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Aquaporin-9 (AQP9).	[6]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Aquaporin-9 (AQP9).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Aquaporin-9 (AQP9).	[10]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Aquaporin-9 (AQP9).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Aquaporin-9 (AQP9).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Aquaporin-9 (AQP9).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Aquaporin-9 (AQP9).	[13]

References

• [1] 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.
• [2] Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. Blood. 2007 Jan 15;109(2):740-6. doi: 10.1182/blood-2006-04-019588. Epub 2006 Sep 12.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study. Environ Health. 2013 Jul 16;12:58. doi: 10.1186/1476-069X-12-58.
• [5] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [6] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9. J Hematol Oncol. 2015 May 8;8:46. doi: 10.1186/s13045-015-0143-3.
• [9] Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9. Biochem Biophys Res Commun. 2004 Sep 24;322(3):836-41. doi: 10.1016/j.bbrc.2004.08.002.
• [10] Altered aquaporin expression in women with polycystic ovary syndrome: hyperandrogenism in follicular fluid inhibits aquaporin-9 in granulosa cells through the phosphatidylinositol 3-kinase pathway. Hum Reprod. 2010 Jun;25(6):1441-50. doi: 10.1093/humrep/deq078. Epub 2010 Apr 8.
• [11] Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses. J Biol Chem. 2015 Oct 16;290(42):25322-32. doi: 10.1074/jbc.M115.645234. Epub 2015 Aug 20.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Cloning and functional expression of a new aquaporin (AQP9) abundantly expressed in the peripheral leukocytes permeable to water and urea, but not to glycerol. Biochem Biophys Res Commun. 1998 Mar 6;244(1):268-74. doi: 10.1006/bbrc.1998.8252.
• [15] Role of AQP9 in transport of monomethyselenic acid and selenite. Biometals. 2017 Oct;30(5):747-755. doi: 10.1007/s10534-017-0042-x. Epub 2017 Aug 10.