Details of Drug Off-Target (DOT)

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

• DOT Name: Volume-regulated anion channel subunit LRRC8E (LRRC8E)
• Synonyms: Leucine-rich repeat-containing protein 8E
• Gene Name: LRRC8E
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Mental disorder
  Panic disorder
• UniProt ID: LRC8E_HUMAN
• Pfam ID: PF00560 ; PF13855 ; PF12534
• Sequence:
  MIPVAEFKQFTEQQPAFKVLKPWWDVLAEYLTVAMLMIGVFGCTLQVTQDKIICLPNHEL
  QENLSEAPCQQLLPRGIPEQIGALQEVKGLKNNLDLQQYSFINQLCYETALHWYAKYFPY
  LVVIHTLIFMVCTSFWFKFPGTSSKIEHFISILGKCFDSPWTTRALSEVSGENQKGPAAT
  ERAAATIVAMAGTGPGKAGEGEKEKVLAEPEKVVTEPPVVTLLDKKEGEQAKALFEKVKK
  FRMHVEEGDILYTMYIRQTVLKVCKFLAILVYNLVYVEKISFLVACRVETSEVTGYASFC
  CNHTKAHLFSKLAFCYISFVCIYGLTCIYTLYWLFHRPLKEYSFRSVREETGMGDIPDVK
  NDFAFMLHLIDQYDSLYSKRFAVFLSEVSESRLKQLNLNHEWTPEKLRQKLQRNAAGRLE
  LALCMLPGLPDTVFELSEVESLRLEAICDITFPPGLSQLVHLQELSLLHSPARLPFSLQV
  FLRDHLKVMRVKCEELREVPLWVFGLRGLEELHLEGLFPQELARAATLESLRELKQLKVL
  SLRSNAGKVPASVTDVAGHLQRLSLHNDGARLVALNSLKKLAALRELELVACGLERIPHA
  VFSLGALQELDLKDNHLRSIEEILSFQHCRKLVTLRLWHNQIAYVPEHVRKLRSLEQLYL
  SYNKLETLPSQLGLCSGLRLLDVSHNGLHSLPPEVGLLQNLQHLALSYNALEALPEELFF
  CRKLRTLLLGDNQLSQLSPHVGALRALSRLELKGNRLEALPEELGNCGGLKKAGLLVEDT
  LYQGLPAEVRDKMEEE
• Function: Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Mediates efflux of amino acids, such as aspartate, in response to osmotic stress. The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol. Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Also plays a role in lysosome homeostasis by forming functional lysosomal VRAC channels in response to low cytoplasmic ionic strength condition: lysosomal VRAC channels are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Biomarker	[1]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[1]
Mental disorder	DIS3J5R8	Strong	Biomarker	[2]
Panic disorder	DISD3VNY	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[3]

15 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 Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Volume-regulated anion channel subunit LRRC8E (LRRC8E).	[16]

References

• [1] LINC00958 facilitates cervical cancer cell proliferation and metastasis by sponging miR-625-5p to upregulate LRRC8E expression.J Cell Biochem. 2020 Mar;121(3):2500-2509. doi: 10.1002/jcb.29472. Epub 2019 Nov 5.
• [2] Association between genes on chromosome 19p13.2 and panic disorder.Psychiatr Genet. 2016 Dec;26(6):287-292. doi: 10.1097/YPG.0000000000000147.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] 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.
• [10] 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.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.