Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9C4PZ4)

• DOT Name: Claudin-4 (CLDN4)
• Synonyms: Clostridium perfringens enterotoxin receptor; CPE-R; CPE-receptor; Williams-Beuren syndrome chromosomal region 8 protein
• Gene Name: CLDN4
• UniProt ID: CLD4_HUMAN
• PDB ID: 5B2G; 7KP4; 7TDM; 7TDN; 8U4V; 8U5B
• Pfam ID: PF00822
• Sequence:
  MASMGLQVMGIALAVLGWLAVMLCCALPMWRVTAFIGSNIVTSQTIWEGLWMNCVVQSTG
  QMQCKVYDSLLALPQDLQAARALVIISIIVAALGVLLSVVGGKCTNCLEDESAKAKTMIV
  AGVVFLLAGLMVIVPVSWTAHNIIQDFYNPLVASGQKREMGASLYVGWAASGLLLLGGGL
  LCCNCPPRTDKPYSAKYSAARSAAASNYV
• Function: Channel-forming tight junction protein that mediates paracellular chloride transport in the kidney. Plays a critical role in the paracellular reabsorption of filtered chloride in the kidney collecting ducts. Claudins play a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)
  Pathogenic Escherichia coli infection (hsa05130)
  Hepatitis C (hsa05160)
• Reactome Pathway: Tight junction interactions (R-HSA-420029)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Claudin-4 (CLDN4) increases the import of Cisplatin.	[31]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Claudin-4 (CLDN4) decreases the response to substance of Arsenic trioxide.	[32]

32 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 Claudin-4 (CLDN4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Claudin-4 (CLDN4).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Claudin-4 (CLDN4).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Claudin-4 (CLDN4).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Claudin-4 (CLDN4).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Claudin-4 (CLDN4).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Claudin-4 (CLDN4).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Claudin-4 (CLDN4).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Claudin-4 (CLDN4).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Claudin-4 (CLDN4).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Claudin-4 (CLDN4).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Claudin-4 (CLDN4).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Claudin-4 (CLDN4).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Claudin-4 (CLDN4).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Claudin-4 (CLDN4).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Claudin-4 (CLDN4).	[16]
Sanguinarine	DMDINFS	Approved	Sanguinarine decreases the expression of Claudin-4 (CLDN4).	[17]
Leuprorelin acetate	DM15HAT	Approved	Leuprorelin acetate decreases the expression of Claudin-4 (CLDN4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Claudin-4 (CLDN4).	[18]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Claudin-4 (CLDN4).	[19]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Claudin-4 (CLDN4).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Claudin-4 (CLDN4).	[4]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Claudin-4 (CLDN4).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Claudin-4 (CLDN4).	[4]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Claudin-4 (CLDN4).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the expression of Claudin-4 (CLDN4).	[24]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Claudin-4 (CLDN4).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Claudin-4 (CLDN4).	[26]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Claudin-4 (CLDN4).	[27]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Claudin-4 (CLDN4).	[28]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Claudin-4 (CLDN4).	[29]
U0126	DM31OGF	Investigative	U0126 increases the expression of Claudin-4 (CLDN4).	[16]

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 Claudin-4 (CLDN4).	[22]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PATULIN	DM0RV9C	Investigative	PATULIN affects the localization of Claudin-4 (CLDN4).	[30]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [5] Arsenic compromises conducting airway epithelial barrier properties in primary mouse and immortalized human cell cultures. PLoS One. 2013 Dec 6;8(12):e82970. doi: 10.1371/journal.pone.0082970. eCollection 2013.
• [6] Quercetin enhances epithelial barrier function and increases claudin-4 expression in Caco-2 cells. J Nutr. 2008 Jun;138(6):1067-73. doi: 10.1093/jn/138.6.1067.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Testosterone regulates tight junction proteins and influences prostatic autoimmune responses. Horm Cancer. 2011 Jun;2(3):145-56. doi: 10.1007/s12672-010-0063-1.
• [9] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [10] 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.
• [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] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [13] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [14] 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.
• [15] Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK. Environ Toxicol. 2020 Dec;35(12):1318-1325. doi: 10.1002/tox.22996. Epub 2020 Jul 13.
• [16] Troglitazone increases expression of E-cadherin and claudin 4 in human pancreatic cancer cells. Biochem Biophys Res Commun. 2009 Mar 13;380(3):614-9. doi: 10.1016/j.bbrc.2009.01.134. Epub 2009 Jan 27.
• [17] Anti-invasive activity of sanguinarine through modulation of tight junctions and matrix metalloproteinase activities in MDA-MB-231 human breast carcinoma cells. Chem Biol Interact. 2009 May 15;179(2-3):185-91. doi: 10.1016/j.cbi.2008.11.009. Epub 2008 Nov 21.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [20] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [21] Defective TPA signalling compromises HaCat cells as a human in vitro skin carcinogenesis model. Toxicol In Vitro. 2010 Apr;24(3):910-5. doi: 10.1016/j.tiv.2009.11.017. Epub 2009 Nov 27.
• [22] 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.
• [23] 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.
• [24] A synthetic coumarin derivative (4-flourophenylacetamide-acetyl coumarin) impedes cell cycle at G0/G1 stage, induces apoptosis, and inhibits metastasis via ROS-mediated p53 and AKT signaling pathways in A549 cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22553. doi: 10.1002/jbt.22553. Epub 2020 Jun 24.
• [25] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [26] Mycotoxins modify the barrier function of Caco-2 cells through differential gene expression of specific claudin isoforms: Protective effect of illite mineral clay. Toxicology. 2016 Apr 15;353-354:21-33. doi: 10.1016/j.tox.2016.05.003. Epub 2016 May 3.
• [27] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [28] The marine biotoxin okadaic acid affects intestinal tight junction proteins in human intestinal cells. Toxicol In Vitro. 2019 Aug;58:150-160. doi: 10.1016/j.tiv.2019.03.033. Epub 2019 Mar 26.
• [29] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [30] The mycotoxin patulin, modulates tight junctions in caco-2 cells. Toxicol In Vitro. 2009 Feb;23(1):83-9. doi: 10.1016/j.tiv.2008.10.009. Epub 2008 Oct 29.
• [31] Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. Mol Pharmacol. 2013 Jan;83(1):85-94. doi: 10.1124/mol.112.079798. Epub 2012 Oct 10.
• [32] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.