Details of Drug Off-Target (DOT)

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

• DOT Name: H(+)/Cl(-) exchange transporter 3 (CLCN3)
• Synonyms: Chloride channel protein 3; ClC-3; Chloride transporter ClC-3
• Gene Name: CLCN3
• Related Disease:
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder with hypotonia and brain abnormalities
  Neurodevelopmental disorder with seizures and brain abnormalities
• UniProt ID: CLCN3_HUMAN
• Pfam ID: PF00571 ; PF00654
• Sequence:
  MESEQLFHRGYYRNSYNSITSASSDEELLDGAGVIMDFQTSEDDNLLDGDTAVGTHYTMT
  NGGSINSSTHLLDLLDEPIPGVGTYDDFHTIDWVREKCKDRERHRRINSKKKESAWEMTK
  SLYDAWSGWLVVTLTGLASGALAGLIDIAADWMTDLKEGICLSALWYNHEQCCWGSNETT
  FEERDKCPQWKTWAELIIGQAEGPGSYIMNYIMYIFWALSFAFLAVSLVKVFAPYACGSG
  IPEIKTILSGFIIRGYLGKWTLMIKTITLVLAVASGLSLGKEGPLVHVACCCGNIFSYLF
  PKYSTNEAKKREVLSAASAAGVSVAFGAPIGGVLFSLEEVSYYFPLKTLWRSFFAALVAA
  FVLRSINPFGNSRLVLFYVEYHTPWYLFELFPFILLGVFGGLWGAFFIRANIAWCRRRKS
  TKFGKYPVLEVIIVAAITAVIAFPNPYTRLNTSELIKELFTDCGPLESSSLCDYRNDMNA
  SKIVDDIPDRPAGIGVYSAIWQLCLALIFKIIMTVFTFGIKVPSGLFIPSMAIGAIAGRI
  VGIAVEQLAYYHHDWFIFKEWCEVGADCITPGLYAMVGAAACLGGVTRMTVSLVVIVFEL
  TGGLEYIVPLMAAVMTSKWVGDAFGREGIYEAHIRLNGYPFLDAKEEFTHTTLAADVMRP
  RRNDPPLAVLTQDNMTVDDIENMINETSYNGFPVIMSKESQRLVGFALRRDLTIAIESAR
  KKQEGIVGSSRVCFAQHTPSLPAESPRPLKLRSILDMSPFTVTDHTPMEIVVDIFRKLGL
  RQCLVTHNGRLLGIITKKDILRHMAQTANQDPASIMFN
• Function: [Isoform 1]: Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The presence of conserved gating glutamate residues is typical for family members that function as antiporters ; [Isoform 2]: Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.
• Tissue Specificity: Expressed primarily in tissues derived from neuroectoderm. Within the brain, its expression is particularly evident in the hippocampus, olfactory cortex, and olfactory bulb. Highly expressed in aortic and coronary vascular smooth muscle cells, and aortic endothelial cells. Also expressed in tracheal and alveolar epithelial cells, and intima and media of the pulmonary vessels. Expressed in bronchus and colon (at protein level).
• KEGG Pathway: Neutrophil extracellular trap formation (hsa04613)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[1]
Neurodevelopmental disorder with hypotonia and brain abnormalities	DISIJ1OP	Strong	Autosomal dominant	[1]
Neurodevelopmental disorder with seizures and brain abnormalities	DIS4O7PO	Limited	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	H(+)/Cl(-) exchange transporter 3 (CLCN3) affects the response to substance of Fluorouracil.	[22]
Topotecan	DMP6G8T	Approved	H(+)/Cl(-) exchange transporter 3 (CLCN3) affects the response to substance of Topotecan.	[22]
Mannitol	DMSCDY9	Approved	H(+)/Cl(-) exchange transporter 3 (CLCN3) affects the response to substance of Mannitol.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloride	DM1TJXA	Phase 3	H(+)/Cl(-) exchange transporter 3 (CLCN3) increases the transport of Chloride.	[24]

20 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 H(+)/Cl(-) exchange transporter 3 (CLCN3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[12]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[20]
NPPB	DMFIWAN	Investigative	NPPB increases the expression of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of H(+)/Cl(-) exchange transporter 3 (CLCN3).	[18]

References

• [1] Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders. Am J Hum Genet. 2021 Aug 5;108(8):1450-1465. doi: 10.1016/j.ajhg.2021.06.003. Epub 2021 Jun 28.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] 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.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 5-Nitro-2-(3-phenylpropylamino) benzoic acid induced drug resistance to cisplatin in human erythroleukemia cell lines. Anat Rec (Hoboken). 2011 Jun;294(6):945-52. doi: 10.1002/ar.21392. Epub 2011 Apr 28.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [23] Differential expression and roles of volume-activated chloride channels in control of growth of normal and cancerous nasopharyngeal epithelial cells. Biochem Pharmacol. 2012 Feb 1;83(3):324-34. doi: 10.1016/j.bcp.2011.11.007. Epub 2011 Nov 18.
• [24] ClC-3 is a main component of background chloride channels activated under isotonic conditions by autocrine ATP in nasopharyngeal carcinoma cells. J Cell Physiol. 2011 Oct;226(10):2516-26. doi: 10.1002/jcp.22596.