Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0F7OLN)

• DOT Name: Gap junction beta-1 protein (GJB1)
• Synonyms: Connexin-32; Cx32; GAP junction 28 kDa liver protein
• Gene Name: GJB1
• Related Disease:
  Charcot-Marie-Tooth disease X-linked dominant 1
  X-linked progressive cerebellar ataxia
• UniProt ID: CXB1_HUMAN
• PDB ID: 5KK9; 7ZXM; 7ZXN; 7ZXO; 7ZXP; 7ZXQ; 7ZXT
• Pfam ID: PF00029
• Sequence:
  MNWTGLYTLLSGVNRHSTAIGRVWLSVIFIFRIMVLVVAAESVWGDEKSSFICNTLQPGC
  NSVCYDQFFPISHVRLWSLQLILVSTPALLVAMHVAHQQHIEKKMLRLEGHGDPLHLEEV
  KRHKVHISGTLWWTYVISVVFRLLFEAVFMYVFYLLYPGYAMVRLVKCDVYPCPNTVDCF
  VSRPTEKTVFTVFMLAASGICIILNVAEVVYLIIRACARRAQRRSNPPSRKGSGFGHRLS
  PEYKQNEINKLLSEQDGSLKDILRRSPGTGAGLAEKSDRCSAC
• Function: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
• Reactome Pathway:
  Transport of connexins along the secretory pathway (R-HSA-190827)
  Gap junction assembly (R-HSA-190861)
  Oligomerization of connexins into connexons (R-HSA-190704)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease X-linked dominant 1	DISC6S1R	Definitive	X-linked	[1]
X-linked progressive cerebellar ataxia	DISVLG2P	Supportive	X-linked	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Gap junction beta-1 protein (GJB1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gap junction beta-1 protein (GJB1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gap junction beta-1 protein (GJB1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gap junction beta-1 protein (GJB1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gap junction beta-1 protein (GJB1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Gap junction beta-1 protein (GJB1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Gap junction beta-1 protein (GJB1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Gap junction beta-1 protein (GJB1).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Gap junction beta-1 protein (GJB1).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Gap junction beta-1 protein (GJB1).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Gap junction beta-1 protein (GJB1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Gap junction beta-1 protein (GJB1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gap junction beta-1 protein (GJB1).	[14]
Fucoxanthin	DMPQFTA	Phase 2	Fucoxanthin increases the expression of Gap junction beta-1 protein (GJB1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gap junction beta-1 protein (GJB1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Gap junction beta-1 protein (GJB1).	[18]

1 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 Gap junction beta-1 protein (GJB1).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Hum Mol Genet. 2013 Nov 1;22(21):4329-38. doi: 10.1093/hmg/ddt282. Epub 2013 Jun 16.
• [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] [Effects of all-trans retinoic acid on expression of connexin genes and gap junction communication in hepatocellular carcinoma cell lines]. Zhonghua Yi Xue Za Zhi. 2005 Jun 1;85(20):1414-8.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] 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.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Inhibition of proliferation of a hepatoma cell line by fucoxanthin in relation to cell cycle arrest and enhanced gap junctional intercellular communication. Chem Biol Interact. 2009 Dec 10;182(2-3):165-72. doi: 10.1016/j.cbi.2009.08.017. Epub 2009 Sep 6.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.