Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPM7BYM)

• DOT Name: Kazrin (KAZN)
• Gene Name: KAZN
• Related Disease:
  Alzheimer disease
  Major depressive disorder
  Metastatic malignant neoplasm
  Mood disorder
  Type-1/2 diabetes
  Thyroid gland papillary carcinoma
  Thyroid tumor
• UniProt ID: KAZRN_HUMAN
• Pfam ID: PF00536 ; PF07647
• Sequence:
  MMEDNKQLALRIDGAVQSASQEVTNLRAELTATNRRLAELSGGGGPGPGPGAAASASAAG
  DSAATNMENPQLGAQVLLREEVSRLQEEVHLLRQMKEMLAKDLEESQGGKSSEVLSATEL
  RVQLAQKEQELARAKEALQAMKADRKRLKGEKTDLVSQMQQLYATLESREEQLRDFIRNY
  EQHRKESEDAVKALAKEKDLLEREKWELRRQAKEATDHATALRSQLDLKDNRMKELEAEL
  AMAKQSLATLTKDVPKRHSLAMPGETVLNGNQEWVVQADLPLTAAIRQSQQTLYHSHPPH
  PADRQAVRVSPCHSRQPSVISDASAAEGDRSSTPSDINSPRHRTHSLCNGDSPGPVQKNL
  HNPIVQSLEDLEDQKRKKKKEKMGFGSISRVFARGKQRKSLDPGLFDDSDSQCSPTRQSL
  SLSEGEEQMDRLQQVELVRTTPMSHWKAGTVQAWLEVVMAMPMYVKACTENVKSGKVLLS
  LSDEDLQLGLGVCSSLHRRKLRLAIEDYRDAEAGRSLSKAAELDHHWVAKAWLNDIGLSQ
  YSQAFQNHLVDGRMLNSLMKRDLEKHLNVSKKFHQVSILLGIELLYQVNFSREALQERRA
  RCETQNIDPVVWTNQRVLKWVRDIDLKEYADNLTNSGVHGAVLVLEPTFNAEAMATALGI
  PSGKHILRRHLAEEMSAVFHPANSTGIREAERFGTPPGRASSVTRAGKEENSSGLKYKAG
  RLPLGKIGRGFSSKDPDFHDDYGSLQNEDCGDDDPQSRLEQCRLEGYNSLEVTNV
• Function: Component of the cornified envelope of keratinocytes. May be involved in the interplay between adherens junctions and desmosomes. The function in the nucleus is not known.
• Tissue Specificity: Isoform 2, isoform 3 and isoform 4 are expressed in several cell lines including keratinocytes and bladder and epidermoid carcinoma (at protein level). Isoform 2, isoform 3 and isoform 4 are expressed in hair follicle and interfollicular epidermis (at protein level).
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[5]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[6]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Kazrin (KAZN) affects the response to substance of Doxorubicin.	[20]
Mitomycin	DMH0ZJE	Approved	Kazrin (KAZN) affects the response to substance of Mitomycin.	[20]
Vinblastine	DM5TVS3	Approved	Kazrin (KAZN) affects the response to substance of Vinblastine.	[20]
Chlorothiazide	DMLHESP	Approved	Kazrin (KAZN) increases the Neutropenia ADR of Chlorothiazide.	[21]

11 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 Kazrin (KAZN).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kazrin (KAZN).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kazrin (KAZN).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kazrin (KAZN).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kazrin (KAZN).	[12]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Kazrin (KAZN).	[13]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Kazrin (KAZN).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Kazrin (KAZN).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kazrin (KAZN).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kazrin (KAZN).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Kazrin (KAZN).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kazrin (KAZN).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Kazrin (KAZN).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Kazrin (KAZN).	[16]

References

• [1] Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.Alzheimers Dement. 2018 May;14(5):623-633. doi: 10.1016/j.jalz.2017.11.006. Epub 2017 Dec 20.
• [2] GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.Am J Psychiatry. 2019 Aug 1;176(8):651-660. doi: 10.1176/appi.ajp.2019.18080957. Epub 2019 Jun 5.
• [3] Genetic background of different cancer cell lines influences the gene set involved in chromosome 8 mediated breast tumor suppression.Genes Chromosomes Cancer. 2006 Jun;45(6):612-27. doi: 10.1002/gcc.20325.
• [4] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [5] Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.Nat Commun. 2019 Sep 11;10(1):4130. doi: 10.1038/s41467-019-11576-0.
• [6] Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases.Endocr Relat Cancer. 2015 Apr;22(2):205-16. doi: 10.1530/ERC-14-0351. Epub 2015 Feb 17.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [14] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [18] 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.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [21] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.