Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7IIWXG)

• DOT Name: Claudin-8 (CLDN8)
• Gene Name: CLDN8
• Related Disease:
  Alzheimer disease
  Bone osteosarcoma
  Colitis
  Colorectal carcinoma
  Crohn disease
  Inflammatory bowel disease
  Kidney neoplasm
  Osteosarcoma
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Retinoblastoma
  Gordon syndrome
  Pseudohypoaldosteronism type 2
  Atopic dermatitis
  Clear cell renal carcinoma
  Colorectal neoplasm
  Neoplasm
• UniProt ID: CLD8_HUMAN
• Pfam ID: PF00822
• Sequence:
  MATHALEIAGLFLGGVGMVGTVAVTVMPQWRVSAFIENNIVVFENFWEGLWMNCVRQANI
  RMQCKIYDSLLALSPDLQAARGLMCAASVMSFLAFMMAILGMKCTRCTGDNEKVKAHILL
  TAGIIFIITGMVVLIPVSWVANAIIRDFYNSIVNVAQKRELGEALYLGWTTALVLIVGGA
  LFCCVFCCNEKSSSYRYSIPSHRTTQKSYHTGKKSPSVYSRSQYV
• Function: Tight-junction protein required for paracellular chloride transport in the kidney. Mediates recruitment of CLDN4 to tight junction in the kidney. Claudins play a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
• Tissue Specificity: Expressed in the epididymis, mainly in the caput segment.
• 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

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[6]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[9]
Gordon syndrome	DISVMP0Y	moderate	Biomarker	[10]
Pseudohypoaldosteronism type 2	DISFTCHO	moderate	Biomarker	[10]
Atopic dermatitis	DISTCP41	Limited	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[6]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Claudin-8 (CLDN8).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Claudin-8 (CLDN8).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Claudin-8 (CLDN8).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Claudin-8 (CLDN8).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Claudin-8 (CLDN8).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Claudin-8 (CLDN8).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Claudin-8 (CLDN8).	[18]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Claudin-8 (CLDN8).	[16]
Tetracycline	DMZA017	Approved	Tetracycline decreases the expression of Claudin-8 (CLDN8).	[19]
Leuprorelin acetate	DM15HAT	Approved	Leuprorelin acetate decreases the expression of Claudin-8 (CLDN8).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Claudin-8 (CLDN8).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Claudin-8 (CLDN8).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Claudin-8 (CLDN8).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Claudin-8 (CLDN8).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Claudin-8 (CLDN8).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Claudin-8 (CLDN8).	[24]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Claudin-8 (CLDN8).	[25]

References

• [1] Reduction of chromatin assembly factor 1 p60 and C21orf2 protein, encoded on chromosome 21, in Down syndrome brain.J Neural Transm Suppl. 2003;(67):117-28. doi: 10.1007/978-3-7091-6721-2_10.
• [2] Transcription Factor SOX9 Promotes Osteosarcoma Cell Growth by Repressing Claudin-8 Expression.Tohoku J Exp Med. 2017 Jan;241(1):55-63. doi: 10.1620/tjem.241.55.
• [3] Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease.Genome Biol. 2016 Mar 30;17:58. doi: 10.1186/s13059-016-0901-8.
• [4] CLDN8 promotes colorectal cancer cell proliferation, migration, and invasion by activating MAPK/ERK signaling.Cancer Manag Res. 2019 Apr 30;11:3741-3751. doi: 10.2147/CMAR.S189558. eCollection 2019.
• [5] Cytokine IL9 Triggers the Pathogenesis of Inflammatory Bowel Disease Through the miR21-CLDN8 Pathway.Inflamm Bowel Dis. 2018 Sep 15;24(10):2211-2223. doi: 10.1093/ibd/izy187.
• [6] Immunohistochemical diagnosis of renal neoplasms.Arch Pathol Lab Med. 2011 Jan;135(1):92-109. doi: 10.5858/2010-0478-RAR.1.
• [7] Epithelial tight junction proteins as potential antibody targets for pancarcinoma therapy.Cancer Immunol Immunother. 2005 May;54(5):431-45. doi: 10.1007/s00262-004-0613-x. Epub 2004 Oct 16.
• [8] CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration.Cancer Sci. 2017 Jul;108(7):1386-1393. doi: 10.1111/cas.13269. Epub 2017 Jun 2.
• [9] MiR-361-5p inhibits cell proliferation and induces cell apoptosis in retinoblastoma by negatively regulating CLDN8.Childs Nerv Syst. 2019 Aug;35(8):1303-1311. doi: 10.1007/s00381-019-04199-9. Epub 2019 Jun 3.
• [10] Paracellular transport in the collecting duct.Curr Opin Nephrol Hypertens. 2016 Sep;25(5):424-8. doi: 10.1097/MNH.0000000000000253.
• [11] Oral treatment with Aloe polysaccharide ameliorates ovalbumin-induced atopic dermatitis by restoring tight junctions in skin.Scand J Immunol. 2020 Mar;91(3):e12856. doi: 10.1111/sji.12856. Epub 2019 Dec 19.
• [12] Differential expression of genes encoding tight junction proteins in colorectal cancer: frequent dysregulation of claudin-1, -8 and -12.Int J Colorectal Dis. 2007 Jun;22(6):651-9. doi: 10.1007/s00384-006-0197-3. Epub 2006 Oct 18.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] 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.
• [15] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [16] Prevention of murine experimental corneal trauma by epigenetic events regulating claudin 6 and claudin 9. Jpn J Ophthalmol. 2008 May-Jun;52(3):195-203. doi: 10.1007/s10384-008-0524-z. Epub 2008 Jul 27.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [19] Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells. Food Chem Toxicol. 2017 Nov;109(Pt 1):253-263. doi: 10.1016/j.fct.2017.09.004. Epub 2017 Sep 4.
• [20] 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.
• [21] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [22] Comparative mechanisms of PAH toxicity by benzo[a]pyrene and dibenzo[def,p]chrysene in primary human bronchial epithelial cells cultured at air-liquid interface. Toxicol Appl Pharmacol. 2019 Sep 15;379:114644.
• [23] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.