Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPON2CI)

• DOT Name: Volume-regulated anion channel subunit LRRC8D (LRRC8D)
• Synonyms: Leucine-rich repeat-containing protein 5; Leucine-rich repeat-containing protein 8D; HsLRRC8D
• Gene Name: LRRC8D
• Related Disease:
  Inflammatory bowel disease
  Intestinal disorder
  Lung squamous cell carcinoma
• UniProt ID: LRC8D_HUMAN
• PDB ID: 6M04
• Pfam ID: PF13855 ; PF12534
• Sequence:
  MFTLAEVASLNDIQPTYRILKPWWDVFMDYLAVVMLMVAIFAGTMQLTKDQVVCLPVLPS
  PVNSKAHTPPGNAEVTTNIPKMEAATNQDQDGRTTNDISFGTSAVTPDIPLRATYPRTDF
  ALPNQEAKKEKKDPTGRKTNLDFQQYVFINQMCYHLALPWYSKYFPYLALIHTIILMVSS
  NFWFKYPKTCSKVEHFVSILGKCFESPWTTKALSETACEDSEENKQRITGAQTLPKHVST
  SSDEGSPSASTPMINKTGFKFSAEKPVIEVPSMTILDKKDGEQAKALFEKVRKFRAHVED
  SDLIYKLYVVQTVIKTAKFIFILCYTANFVNAISFEHVCKPKVEHLIGYEVFECTHNMAY
  MLKKLLISYISIICVYGFICLYTLFWLFRIPLKEYSFEKVREESSFSDIPDVKNDFAFLL
  HMVDQYDQLYSKRFGVFLSEVSENKLREISLNHEWTFEKLRQHISRNAQDKQELHLFMLS
  GVPDAVFDLTDLDVLKLELIPEAKIPAKISQMTNLQELHLCHCPAKVEQTAFSFLRDHLR
  CLHVKFTDVAEIPAWVYLLKNLRELYLIGNLNSENNKMIGLESLRELRHLKILHVKSNLT
  KVPSNITDVAPHLTKLVIHNDGTKLLVLNSLKKMMNVAELELQNCELERIPHAIFSLSNL
  QELDLKSNNIRTIEEIISFQHLKRLTCLKLWHNKIVTIPPSITHVKNLESLYFSNNKLES
  LPVAVFSLQKLRCLDVSYNNISMIPIEIGLLQNLQHLHITGNKVDILPKQLFKCIKLRTL
  NLGQNCITSLPEKVGQLSQLTQLELKGNCLDRLPAQLGQCRMLKKSGLVVEDHLFDTLPL
  EVKEALNQDINIPFANGI
• 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, in response to osmotic stress. LRRC8A and LRRC8D are required for the uptake of the drug cisplatin. 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 acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion. VRAC channels containing LRRC8D inhibit transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol. Mediates the import of the antibiotic blasticidin-S into the cell.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammatory bowel disease	DISGN23E	Disputed	Genetic Variation	[1]
Intestinal disorder	DISGPMUQ	Disputed	Genetic Variation	[1]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[13]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Volume-regulated anion channel subunit LRRC8D (LRRC8D).	[14]

References

• [1] NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.J Gastroenterol. 2018 Sep;53(9):1065-1078. doi: 10.1007/s00535-018-1486-7. Epub 2018 Jun 19.
• [2] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] 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.
• [8] 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.
• [9] 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.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] 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.
• [14] 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.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.