Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGUGAF9)

• DOT Name: Haptoglobin (HP)
• Synonyms: Zonulin
• Gene Name: HP
• UniProt ID: HPT_HUMAN
• PDB ID: 4WJG; 4X0L; 5HU6; 6TB2
• Pfam ID: PF00089
• Sequence:
  MSALGAVIALLLWGQLFAVDSGNDVTDIADDGCPKPPEIAHGYVEHSVRYQCKNYYKLRT
  EGDGVYTLNDKKQWINKAVGDKLPECEADDGCPKPPEIAHGYVEHSVRYQCKNYYKLRTE
  GDGVYTLNNEKQWINKAVGDKLPECEAVCGKPKNPANPVQRILGGHLDAKGSFPWQAKMV
  SHHNLTTGATLINEQWLLTTAKNLFLNHSENATAKDIAPTLTLYVGKKQLVEIEKVVLHP
  NYSQVDIGLIKLKQKVSVNERVMPICLPSKDYAEVGRVGYVSGWGRNANFKFTDHLKYVM
  LPVADQDQCIRHYEGSTVPEKKTPKSPVGVQPILNEHTFCAGMSKYQEDTCYGDAGSAFA
  VHDLEEDTWYATGILSFDKSCAVAEYGVYVKVTSIQDWVQKTIAEN
• Function: As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine. Haptoglobin captures, and combines with free plasma hemoglobin to allow hepatic recycling of heme iron and to prevent kidney damage. Haptoglobin also acts as an antioxidant, has antibacterial activity, and plays a role in modulating many aspects of the acute phase response. Hemoglobin/haptoglobin complexes are rapidly cleared by the macrophage CD163 scavenger receptor expressed on the surface of liver Kupfer cells through an endocytic lysosomal degradation pathway; The uncleaved form of allele alpha-2 (2-2), known as zonulin, plays a role in intestinal permeability, allowing intercellular tight junction disassembly, and controlling the equilibrium between tolerance and immunity to non-self antigens.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Scavenging of heme from plasma (R-HSA-2168880)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin C	DMXJ7O8	Approved	Haptoglobin (HP) affects the response to substance of Vitamin C.	[20]
Ribavirin	DMEYLH9	Phase 1 Trial	Haptoglobin (HP) increases the Hepatic function abnormal ADR of Ribavirin.	[21]

1 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 Haptoglobin (HP).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Haptoglobin (HP).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Haptoglobin (HP).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Haptoglobin (HP).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Haptoglobin (HP).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Haptoglobin (HP).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Haptoglobin (HP).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Haptoglobin (HP).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Haptoglobin (HP).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Haptoglobin (HP).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Haptoglobin (HP).	[11]
Penicillamine	DM40EF6	Approved	Penicillamine decreases the expression of Haptoglobin (HP).	[12]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Haptoglobin (HP).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Haptoglobin (HP).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol affects the activity of Haptoglobin (HP).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Haptoglobin (HP).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Haptoglobin (HP).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Haptoglobin (HP).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose affects the secretion of Haptoglobin (HP).	[19]

References

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• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [8] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] 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.
• [11] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [12] The influence of alclofenac treatment on acute-phase proteins, plasma tryptophan, and erythrocyte sedimentation rate in patients with rheumatoid arthritis. Curr Med Res Opin. 1975;3(5):286-97. doi: 10.1185/03007997509114779.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype. Antioxid Redox Signal. 2010 Feb;12(2):209-17. doi: 10.1089/ars.2009.2829.
• [16] Identification of AhR-regulated genes involved in PAH-induced immunotoxicity using a highly-sensitive DNA chip, 3D-Gene human immunity and metabolic syndrome 9k. Toxicol In Vitro. 2010 Feb;24(1):85-91.
• [17] Microarray analysis of bisphenol A-induced changes in gene expression in human oral epithelial cells. Acta Biochim Biophys Sin (Shanghai). 2007 Nov;39(11):879-84. doi: 10.1111/j.1745-7270.2007.00351.x.
• [18] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [19] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [20] Haptoglobin genotype modifies the association between dietary vitamin C and serum ascorbic acid deficiency. Am J Clin Nutr. 2010 Dec;92(6):1494-500. doi: 10.3945/ajcn.2010.29306. Epub 2010 Oct 6.
• [21] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.