Details of Drug Off-Target (DOT)

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

• DOT Name: Loricrin (LORICRIN)
• Gene Name: LORICRIN
• Related Disease:
  Lung adenocarcinoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Breast carcinoma
  Crohn disease
  Disease of orbital part of eye adnexa
  Erythrokeratoderma
  Erythrokeratodermia variabilis
  Keratoderma hereditarium mutilans
  Loricrin keratoderma
  Metastatic malignant neoplasm
  Neoplasm
  Primary biliary cholangitis
  Skin disease
  Squamous cell carcinoma
  Congenital ichthyosiform erythroderma
  Skin cancer
  Skin neoplasm
  Atopic dermatitis
  Cardiomyopathy
• UniProt ID: LORI_HUMAN
• Pfam ID: PF15847
• Sequence:
  MSYQKKQPTPQPPVDCVKTSGGGGGGGGSGGGGCGFFGGGGSGGGSSGSGCGYSGGGGYS
  GGGCGGGSSGGGGGGGIGGCGGGSGGSVKYSGGGGSSGGGSGCFSSGGGGSGCFSSGGGG
  SSGGGSGCFSSGGGGSSGGGSGCFSSGGGGFSGQAVQCQSYGGVSSGGSSGGGSGCFSSG
  GGGGSVCGYSGGGSGCGGGSSGGSGSGYVSSQQVTQTSCAPQPSYGGGSSGGGGSGGSGC
  FSSGGGGGSSGCGGGSSGIGSGCIISGGGSVCGGGSSGGGGGGSSVGGSGSGKGVPICHQ
  TQQKQAPTWPSK
• Function: Major keratinocyte cell envelope protein.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Genetic Variation	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[4]
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[5]
Erythrokeratoderma	DISQGG08	Strong	Genetic Variation	[6]
Erythrokeratodermia variabilis	DIS4BMUQ	Strong	Genetic Variation	[7]
Keratoderma hereditarium mutilans	DIS8KG10	Strong	Biomarker	[8]
Loricrin keratoderma	DIS18PKK	Strong	Autosomal dominant	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Primary biliary cholangitis	DIS43E0O	Strong	Altered Expression	[11]
Skin disease	DISDW8R6	Strong	Genetic Variation	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[13]
Congenital ichthyosiform erythroderma	DISV8HQX	moderate	Genetic Variation	[14]
Skin cancer	DISTM18U	moderate	Biomarker	[13]
Skin neoplasm	DIS16DDV	moderate	Biomarker	[13]
Atopic dermatitis	DISTCP41	Limited	Altered Expression	[15]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[16]

7 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 Loricrin (LORICRIN).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Loricrin (LORICRIN).	[18]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Loricrin (LORICRIN).	[19]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Loricrin (LORICRIN).	[19]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Loricrin (LORICRIN).	[20]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the expression of Loricrin (LORICRIN).	[22]
PD98059	DMZC90M	Investigative	PD98059 increases the expression of Loricrin (LORICRIN).	[22]

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 increases the methylation of Loricrin (LORICRIN).	[21]

References

• [1] Olmsted syndrome with squamous cell carcinoma of extremities and adenocarcinoma of the lung: failure to detect loricrin gene mutation.Eur J Dermatol. 2003 Nov-Dec;13(6):524-8.
• [2] Mechanism of leukemogenesis by human T-cell leukemia virus types I and II: role of the lor gene.Cancer Detect Prev. 1987;10(5-6):411-24.
• [3] Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo.Cancer Res. 2003 Apr 1;63(7):1657-66.
• [4] Anti-TNF Re-induction Is as Effective, Simpler, and Cheaper Compared With Dose Interval Shortening for Secondary Loss of Response in Crohn's Disease.J Crohns Colitis. 2018 Feb 28;12(3):280-288. doi: 10.1093/ecco-jcc/jjx144.
• [5] Difference in Midface Rejuvenation Strategy Between East Asians and Caucasians Based on Analysis of Age-related Changes in the Orbit and Midcheek Using Computed Tomography.Aesthetic Plast Surg. 2019 Dec;43(6):1547-1552. doi: 10.1007/s00266-019-01478-3. Epub 2019 Aug 29.
• [6] Abnormal cornified cell envelope formation in mutilating palmoplantar keratoderma unrelated to epidermal differentiation complex.J Invest Dermatol. 1998 Jul;111(1):133-8. doi: 10.1046/j.1523-1747.1998.00230.x.
• [7] No exonic mutations at GJB2, GJB3, GJB4, GJB6, ARS (Component B), and LOR genes responsible for a Chinese patient affected by progressive symmetric erythrokeratodermia with pseudoainhum.Int J Dermatol. 2014 Sep;53(9):1111-3. doi: 10.1111/ijd.12494. Epub 2014 Jun 25.
• [8] G59S mutation in the GJB2 gene in a Chinese family with classic Vohwinkel syndrome.J Dermatol. 2019 Feb;46(2):154-157. doi: 10.1111/1346-8138.14727. Epub 2018 Dec 19.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas.Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17202-7. doi: 10.1073/pnas.0604481103. Epub 2006 Nov 1.
• [11] Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005 Sep;43(3):499-507. doi: 10.1016/j.jhep.2005.02.052.
• [12] Activation of vascular endothelial growth factor receptor 2 in a cellular model of loricrin keratoderma.J Biol Chem. 2010 May 21;285(21):16184-94. doi: 10.1074/jbc.M109.056424. Epub 2010 Mar 17.
• [13] Arsenic-induced malignant transformation of human keratinocytes: involvement of Nrf2.Free Radic Biol Med. 2008 Sep 1;45(5):651-8. doi: 10.1016/j.freeradbiomed.2008.05.020. Epub 2008 Jun 3.
• [14] Loricrin keratoderma: a cause of congenital ichthyosiform erythroderma and collodion baby.Br J Dermatol. 2001 Oct;145(4):657-60. doi: 10.1046/j.1365-2133.2001.04412.x.
• [15] Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6.Clin Immunol. 2008 Mar;126(3):332-7. doi: 10.1016/j.clim.2007.11.006. Epub 2007 Dec 31.
• [16] Low lead one ratio predicts clinical outcomes in left bundle branch block.J Cardiovasc Electrophysiol. 2019 May;30(5):709-716. doi: 10.1111/jce.13875. Epub 2019 Feb 19.
• [17] Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J Pharmacol Exp Ther. 2006 Dec;319(3):1162-71.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Retinoic acid and hydroquinone induce inverse expression patterns on cornified envelope-associated proteins: implication in skin irritation. J Dermatol Sci. 2014 Nov;76(2):112-9. doi: 10.1016/j.jdermsci.2014.08.003. Epub 2014 Aug 26.
• [20] Deducing signaling pathways from parallel actions of arsenite and antimonite in human epidermal keratinocytes. Sci Rep. 2020 Feb 19;10(1):2890. doi: 10.1038/s41598-020-59577-0.
• [21] 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.
• [22] Sulfur mustard induces differentiation in human primary keratinocytes: opposite roles of p38 and ERK1/2 MAPK. Toxicol Lett. 2011 Jul 4;204(1):43-51. doi: 10.1016/j.toxlet.2011.04.007. Epub 2011 Apr 15.