Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ2F15Z)

• DOT Name: Hephaestin (HEPH)
• Synonyms: EC 1.-.-.-
• Gene Name: HEPH
• Related Disease:
  Neoplasm
  Non-insulin dependent diabetes
  Anemia
  Breast cancer
  Breast carcinoma
  Cardiac disease
  Cowden disease
  Hemochromatosis
  Hemolytic anemia
  Liver cirrhosis
  Malignant mesothelioma
  Migraine disorder
  Retinitis pigmentosa
  Age-related macular degeneration
  Hereditary hemochromatosis
  Baldness, male pattern
  Nervous system inflammation
  Parkinson disease
• UniProt ID: HEPH_HUMAN
• EC Number: 1.-.-.-
• Pfam ID: PF07731 ; PF07732
• Sequence:
  MESGHLLWALLFMQSLWPQLTDGATRVYYLGIRDVQWNYAPKGRNVITNQPLDSDIVASS
  FLKSDKNRIGGTYKKTIYKEYKDDSYTDEVAQPAWLGFLGPVLQAEVGDVILIHLKNFAT
  RPYTIHPHGVFYEKDSEGSLYPDGSSGPLKADDSVPPGGSHIYNWTIPEGHAPTDADPAC
  LTWIYHSHVDAPRDIATGLIGPLITCKRGALDGNSPPQRQDVDHDFFLLFSVVDENLSWH
  LNENIATYCSDPASVDKEDETFQESNRMHAINGFVFGNLPELNMCAQKRVAWHLFGMGNE
  IDVHTAFFHGQMLTTRGHHTDVANIFPATFVTAEMVPWEPGTWLISCQVNSHFRDGMQAL
  YKVKSCSMAPPVDLLTGKVRQYFIEAHEIQWDYGPMGHDGSTGKNLREPGSISDKFFQKS
  SSRIGGTYWKVRYEAFQDETFQEKMHLEEDRHLGILGPVIRAEVGDTIQVVFYNRASQPF
  SMQPHGVFYEKDYEGTVYNDGSSYPGLVAKPFEKVTYRWTVPPHAGPTAQDPACLTWMYF
  SAADPIRDTNSGLVGPLLVCRAGALGADGKQKGVDKEFFLLFTVLDENKSWYSNANQAAA
  MLDFRLLSEDIEGFQDSNRMHAINGFLFSNLPRLDMCKGDTVAWHLLGLGTETDVHGVMF
  QGNTVQLQGMRKGAAMLFPHTFVMAIMQPDNLGTFEIYCQAGSHREAGMRAIYNVSQCPG
  HQATPRQRYQAARIYYIMAEEVEWDYCPDRSWEREWHNQSEKDSYGYIFLSNKDGLLGSR
  YKKAVFREYTDGTFRIPRPRTGPEEHLGILGPLIKGEVGDILTVVFKNNASRPYSVHAHG
  VLESTTVWPLAAEPGEVVTYQWNIPERSGPGPNDSACVSWIYYSAVDPIKDMYSGLVGPL
  AICQKGILEPHGGRSDMDREFALLFLIFDENKSWYLEENVATHGSQDPGSINLQDETFLE
  SNKMHAINGKLYANLRGLTMYQGERVAWYMLAMGQDVDLHTIHFHAESFLYRNGENYRAD
  VVDLFPGTFEVVEMVASNPGTWLMHCHVTDHVHAGMETLFTVFSRTEHLSPLTVITKETE
  KAVPPRDIEEGNVKMLGMQIPIKNVEMLASVLVAISVTLLLVVLALGGVVWYQHRQRKLR
  RNRRSILDDSFKLLSFKQ
• Function: May function as a ferroxidase for ferrous (II) to ferric ion (III) conversion and may be involved in copper transport and homeostasis. Implicated in iron homeostasis and may mediate iron efflux associated to ferroportin 1.
• Tissue Specificity: Detected in breast, colon, bone trabecular cells and fibroblasts.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) (R-HSA-5655799)
  Iron uptake and transport (R-HSA-917937)
  Metal ion SLC transporters (R-HSA-425410)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Anemia	DISTVL0C	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Cardiac disease	DISVO1I5	Strong	Biomarker	[5]
Cowden disease	DISMYKCE	Strong	Biomarker	[6]
Hemochromatosis	DISAPY0H	Strong	Altered Expression	[7]
Hemolytic anemia	DIS803XQ	Strong	Biomarker	[8]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[9]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[10]
Migraine disorder	DISFCQTG	Strong	Biomarker	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[12]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[13]
Hereditary hemochromatosis	DISVG5MT	Moderate	X-linked	[14]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[15]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[16]
Parkinson disease	DISQVHKL	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Hephaestin (HEPH) affects the response to substance of Etoposide.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Hephaestin (HEPH).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hephaestin (HEPH).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Hephaestin (HEPH).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hephaestin (HEPH).	[20]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Hephaestin (HEPH).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hephaestin (HEPH).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Hephaestin (HEPH).	[22]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Hephaestin (HEPH).	[23]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Hephaestin (HEPH).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Hephaestin (HEPH).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hephaestin (HEPH).	[27]
Manganese	DMKT129	Investigative	Manganese increases the expression of Hephaestin (HEPH).	[28]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Hephaestin (HEPH).	[29]

References

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• [2] Ablation of hephaestin and ceruloplasmin results in iron accumulation in adipocytes and type 2 diabetes.FEBS Lett. 2018 Feb;592(3):394-401. doi: 10.1002/1873-3468.12978. Epub 2018 Jan 31.
• [3] Large scale expression and purification of secreted mouse hephaestin.PLoS One. 2017 Sep 7;12(9):e0184366. doi: 10.1371/journal.pone.0184366. eCollection 2017.
• [4] G9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin.Nat Commun. 2017 Aug 17;8(1):274. doi: 10.1038/s41467-017-00350-9.
• [5] Comparison of the Medtronic SelectSecure and conventional pacing leads: Long-term follow-up in a multicenter pediatric and congenital cohort.Pacing Clin Electrophysiol. 2019 Mar;42(3):356-365. doi: 10.1111/pace.13614. Epub 2019 Feb 8.
• [6] Circularly polarised luminescence of pyrenyl di- and tri-peptides with mixed d- and l-amino acid residues.Org Biomol Chem. 2017 May 31;15(21):4548-4553. doi: 10.1039/c7ob00503b.
• [7] Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis.Gastroenterology. 2003 Sep;125(3):746-54. doi: 10.1016/s0016-5085(03)01063-1.
• [8] Intestinal hephaestin potentiates iron absorption in weanling, adult, and pregnant mice under physiological conditions.Blood Adv. 2017 Jul 25;1(17):1335-1346. doi: 10.1182/bloodadvances.2017008359. eCollection 2017 Jul 25.
• [9] Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis.Hepatology. 2004 Feb;39(2):492-9. doi: 10.1002/hep.20038.
• [10] Iron signature in asbestos-induced malignant pleural mesothelioma: A population-based autopsy study.J Toxicol Environ Health A. 2016;79(3):129-41. doi: 10.1080/15287394.2015.1123452. Epub 2016 Jan 28.
• [11] Ion channelopathies and migraine pathogenesis.Mol Genet Genomics. 2017 Aug;292(4):729-739. doi: 10.1007/s00438-017-1317-1. Epub 2017 Apr 7.
• [12] Altered intra- and inter-regional functional connectivity of the visual cortex in individuals with peripheral vision loss due to retinitis pigmentosa.Vision Res. 2019 Jun;159:68-75. doi: 10.1016/j.visres.2019.02.013. Epub 2019 Apr 16.
• [13] The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration.Invest Ophthalmol Vis Sci. 2011 Feb 16;52(2):959-68. doi: 10.1167/iovs.10-6207.
• [14] 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.
• [15] Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.PLoS Genet. 2012 May;8(5):e1002746. doi: 10.1371/journal.pgen.1002746. Epub 2012 May 31.
• [16] Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.J Neuropathol Exp Neurol. 2017 Jun 1;76(6):467-478. doi: 10.1093/jnen/nlx034.
• [17] Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson's disease.Free Radic Biol Med. 2010 Jan 15;48(2):332-41. doi: 10.1016/j.freeradbiomed.2009.11.004. Epub 2009 Nov 11.
• [18] 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.
• [19] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [20] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [24] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [25] 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.
• [26] 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.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [29] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [30] 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.