Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT607RBL)

• DOT Name: Hepcidin (HAMP)
• Synonyms: Liver-expressed antimicrobial peptide 1; LEAP-1; Putative liver tumor regressor; PLTR
• Gene Name: HAMP
• Related Disease:
  Hemochromatosis type 2B
  Hemochromatosis type 2
• UniProt ID: HEPC_HUMAN
• PDB ID: 1M4E; 1M4F; 2KEF; 3H0T; 4QAE; 6WBV
• Pfam ID: PF06446
• Sequence:
  MALSSQIWAACLLLLLLLASLTSGSVFPQQTGQLAELQPQDRAGARASWMPMFQRRRRRD
  THFPICIFCCGCCHRSKCGMCCKT
• Function: Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues. Acts by promoting endocytosis and degradation of ferroportin/SLC40A1, leading to the retention of iron in iron-exporting cells and decreased flow of iron into plasma. Controls the major flows of iron into plasma: absorption of dietary iron in the intestine, recycling of iron by macrophages, which phagocytose old erythrocytes and other cells, and mobilization of stored iron from hepatocytes ; Has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker against S.epidermidis, S.aureus and group b streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.
• Tissue Specificity: Highest expression in liver and to a lesser extent in heart and brain. Low levels in lung, tonsils, salivary gland, trachea, prostate gland, adrenal gland and thyroid gland. Secreted into the urine and blood . Expressed by hepatocytes .
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemochromatosis type 2B	DISR35MD	Definitive	Autosomal recessive	[1]
Hemochromatosis type 2	DISYM9UP	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Hepcidin (HAMP).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hepcidin (HAMP).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepcidin (HAMP).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Hepcidin (HAMP).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hepcidin (HAMP).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hepcidin (HAMP).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hepcidin (HAMP).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hepcidin (HAMP).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hepcidin (HAMP).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hepcidin (HAMP).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Hepcidin (HAMP).	[12]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Hepcidin (HAMP).	[13]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Hepcidin (HAMP).	[12]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of Hepcidin (HAMP).	[12]
Cantharidin	DMBP5N3	Approved	Cantharidin decreases the expression of Hepcidin (HAMP).	[12]
Methimazole	DM25FL8	Approved	Methimazole decreases the expression of Hepcidin (HAMP).	[14]
Omeprazole	DM471KJ	Approved	Omeprazole increases the expression of Hepcidin (HAMP).	[15]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole increases the expression of Hepcidin (HAMP).	[15]
Papaverine	DMCA9QP	Approved	Papaverine decreases the expression of Hepcidin (HAMP).	[12]
Pantoprazole	DMSVOCZ	Approved	Pantoprazole increases the expression of Hepcidin (HAMP).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hepcidin (HAMP).	[16]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Hepcidin (HAMP).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepcidin (HAMP).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Hepcidin (HAMP).	[17]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the expression of Hepcidin (HAMP).	[12]
KENPAULLONE	DMAGVXW	Patented	KENPAULLONE decreases the expression of Hepcidin (HAMP).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Hepcidin (HAMP).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Hepcidin (HAMP).	[13]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Hepcidin (HAMP).	[19]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Hepcidin (HAMP).	[9]
Forskolin	DM6ITNG	Investigative	Forskolin affects the expression of Hepcidin (HAMP).	[12]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Hepcidin (HAMP).	[20]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Hepcidin (HAMP).	[12]
Apomorphine SL	DMPH7EO	Investigative	Apomorphine SL decreases the expression of Hepcidin (HAMP).	[12]
Benzamil	DM57SVW	Investigative	Benzamil decreases the expression of Hepcidin (HAMP).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
SU9516	DMQHG0R	Investigative	SU9516 decreases the secretion of Hepcidin (HAMP).	[12]

References

• [1] Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003 Jan;33(1):21-2. doi: 10.1038/ng1053. Epub 2002 Dec 9.
• [2] Juvenile Hemochromatosis. 2005 Feb 17 [updated 2020 Jan 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] 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.
• [10] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.
• [13] Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem. 2006 Aug 11;281(32):22974-82. doi: 10.1074/jbc.M602098200. Epub 2006 May 31.
• [14] Blood cell oxidative stress precedes hemolysis in whole blood-liver slice co-cultures of rat, dog, and human tissues. Toxicol Appl Pharmacol. 2010 May 1;244(3):354-65. doi: 10.1016/j.taap.2010.01.017. Epub 2010 Feb 6.
• [15] Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway. Toxicol Lett. 2020 Jan;318:86-91. doi: 10.1016/j.toxlet.2019.10.016. Epub 2019 Oct 24.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [19] Identification of palmitate-regulated genes in HepG2 cells by applying microarray analysis. Biochim Biophys Acta. 2007 Sep;1770(9):1283-8. doi: 10.1016/j.bbagen.2007.07.001. Epub 2007 Jul 10.
• [20] Sublethal exposure of organophosphate pesticide chlorpyrifos alters cellular iron metabolism in hepatocytes and macrophages. Int J Mol Med. 2014 Nov;34(5):1395-400. doi: 10.3892/ijmm.2014.1902. Epub 2014 Aug 18.