Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2Y51BP)

• DOT Name: Volume-regulated anion channel subunit LRRC8C (LRRC8C)
• Synonyms: Factor for adipocyte differentiation 158; Leucine-rich repeat-containing protein 8C
• Gene Name: LRRC8C
• UniProt ID: LRC8C_HUMAN
• PDB ID: 8DXN; 8DXO; 8DXP; 8DXQ; 8DXR
• Pfam ID: PF13855 ; PF12534
• Sequence:
  MIPVTEFRQFSEQQPAFRVLKPWWDVFTDYLSVAMLMIGVFGCTLQVMQDKIICLPKRVQ
  PAQNHSSLSNVSQAVASTTPLPPPKPSPANPITVEMKGLKTDLDLQQYSFINQMCYERAL
  HWYAKYFPYLVLIHTLVFMLCSNFWFKFPGSSSKIEHFISILGKCFDSPWTTRALSEVSG
  EDSEEKDNRKNNMNRSNTIQSGPEDSLVNSQSLKSIPEKFVVDKSTAGALDKKEGEQAKA
  LFEKVKKFRLHVEEGDILYAMYVRQTVLKVIKFLIIIAYNSALVSKVQFTVDCNVDIQDM
  TGYKNFSCNHTMAHLFSKLSFCYLCFVSIYGLTCLYTLYWLFYRSLREYSFEYVRQETGI
  DDIPDVKNDFAFMLHMIDQYDPLYSKRFAVFLSEVSENKLKQLNLNNEWTPDKLRQKLQT
  NAHNRLELPLIMLSGLPDTVFEITELQSLKLEIIKNVMIPATIAQLDNLQELSLHQCSVK
  IHSAALSFLKENLKVLSVKFDDMRELPPWMYGLRNLEELYLVGSLSHDISRNVTLESLRD
  LKSLKILSIKSNVSKIPQAVVDVSSHLQKMCIHNDGTKLVMLNNLKKMTNLTELELVHCD
  LERIPHAVFSLLSLQELDLKENNLKSIEEIVSFQHLRKLTVLKLWHNSITYIPEHIKKLT
  SLERLSFSHNKIEVLPSHLFLCNKIRYLDLSYNDIRFIPPEIGVLQSLQYFSITCNKVES
  LPDELYFCKKLKTLKIGKNSLSVLSPKIGNLLFLSYLDVKGNHFEILPPELGDCRALKRA
  GLVVEDALFETLPSDVREQMKTE
• 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. Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, 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.
• Tissue Specificity: Expressed at highest levels in skeletal muscle, and at moderate levels in heart, lung and peripheral blood leukocytes.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

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 Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Volume-regulated anion channel subunit LRRC8C (LRRC8C).	[15]

References

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• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.