Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9GG3ZI)

• DOT Name: Alpha-fetoprotein (AFP)
• Synonyms: Alpha-1-fetoprotein; Alpha-fetoglobulin
• Gene Name: AFP
• Related Disease:
  Obsolete hereditary persistence of alpha-fetoprotein
  Obsolete congenital deficiency in alpha-fetoprotein
• UniProt ID: FETA_HUMAN
• PDB ID: 3MRK; 7RE7; 7RE8; 7YIM
• Pfam ID: PF00273
• Sequence:
  MKWVESIFLIFLLNFTESRTLHRNEYGIASILDSYQCTAEISLADLATIFFAQFVQEATY
  KEVSKMVKDALTAIEKPTGDEQSSGCLENQLPAFLEELCHEKEILEKYGHSDCCSQSEEG
  RHNCFLAHKKPTPASIPLFQVPEPVTSCEAYEEDRETFMNKFIYEIARRHPFLYAPTILL
  WAARYDKIIPSCCKAENAVECFQTKAATVTKELRESSLLNQHACAVMKNFGTRTFQAITV
  TKLSQKFTKVNFTEIQKLVLDVAHVHEHCCRGDVLDCLQDGEKIMSYICSQQDTLSNKIT
  ECCKLTTLERGQCIIHAENDEKPEGLSPNLNRFLGDRDFNQFSSGEKNIFLASFVHEYSR
  RHPQLAVSVILRVAKGYQELLEKCFQTENPLECQDKGEEELQKYIQESQALAKRSCGLFQ
  KLGEYYLQNAFLVAYTKKAPQLTSSELMAITRKMAATAATCCQLSEDKLLACGEGAADII
  IGHLCIRHEMTPVNPGVGQCCTSSYANRRPCFSSLVVDETYVPPAFSDDKFIFHKDLCQA
  QGVALQTMKQEFLINLVKQKPQITEEQLEAVIADFSGLLEKCCQGQEQEVCFAEEGQKLI
  SKTRAALGV
• Function: Binds copper, nickel, and fatty acids as well as, and bilirubin less well than, serum albumin. Only a small percentage (less than 2%) of the human AFP shows estrogen-binding properties.
• Tissue Specificity: Plasma. Synthesized by the fetal liver and yolk sac.
• KEGG Pathway: Hippo sig.ling pathway (hsa04390)
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete hereditary persistence of alpha-fetoprotein	DIS9WGEZ	Supportive	Autosomal dominant	[1]
Obsolete congenital deficiency in alpha-fetoprotein	DISB8IN0	No Known	Autosomal recessive	[2]

27 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 Alpha-fetoprotein (AFP).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-fetoprotein (AFP).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-fetoprotein (AFP).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-fetoprotein (AFP).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-fetoprotein (AFP).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-fetoprotein (AFP).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Alpha-fetoprotein (AFP).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-fetoprotein (AFP).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Alpha-fetoprotein (AFP).	[11]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Alpha-fetoprotein (AFP).	[12]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Alpha-fetoprotein (AFP).	[13]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Alpha-fetoprotein (AFP).	[14]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Alpha-fetoprotein (AFP).	[15]
Isoniazid	DM5JVS3	Approved	Isoniazid decreases the expression of Alpha-fetoprotein (AFP).	[6]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Alpha-fetoprotein (AFP).	[16]
Estriol	DMOEM2I	Approved	Estriol increases the expression of Alpha-fetoprotein (AFP).	[17]
Urea	DMUK75B	Approved	Urea increases the expression of Alpha-fetoprotein (AFP).	[18]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Alpha-fetoprotein (AFP).	[19]
Benzylpenicillin	DMS9503	Phase 3	Benzylpenicillin decreases the expression of Alpha-fetoprotein (AFP).	[20]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Alpha-fetoprotein (AFP).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Alpha-fetoprotein (AFP).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Alpha-fetoprotein (AFP).	[22]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Alpha-fetoprotein (AFP).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alpha-fetoprotein (AFP).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Alpha-fetoprotein (AFP).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Alpha-fetoprotein (AFP).	[6]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate decreases the expression of Alpha-fetoprotein (AFP).	[25]

References

• [1] A G-->A substitution in an HNF I binding site in the human alpha-fetoprotein gene is associated with hereditary persistence of alpha-fetoprotein (HPAFP). Hum Mol Genet. 1993 Apr;2(4):379-84. doi: 10.1093/hmg/2.4.379.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Expression of AFP and STAT3 is involved in arsenic trioxide-induced apoptosis and inhibition of proliferation in AFP-producing gastric cancer cells. PLoS One. 2013;8(1):e54774. doi: 10.1371/journal.pone.0054774. Epub 2013 Jan 30.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [12] Self-assembled 3D spheroids and hollow-fibre bioreactors improve MSC-derived hepatocyte-like cell maturation in vitro. Arch Toxicol. 2017 Apr;91(4):1815-1832.
• [13] Effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on alpha-fetoprotein gene expression through interaction with the ras-mediated pathway. J Hepatol. 1999 May;30(5):904-10. doi: 10.1016/s0168-8278(99)80146-9.
• [14] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [15] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [16] Low-expressional IGF1 mediated methimazole-induced liver developmental toxicity in fetal mice. Toxicology. 2018 Sep 1;408:70-79. doi: 10.1016/j.tox.2018.07.004. Epub 2018 Jul 7.
• [17] Hormones of pregnancy, alpha-feto protein, and reduction of breast cancer risk. Adv Exp Med Biol. 2008;617:477-84. doi: 10.1007/978-0-387-69080-3_47.
• [18] Carcinoembryonic antigen, alpha-fetoprotein, and prostate-specific antigen in the sera of industrial workers exposed to phenol, formaldehyde, urea, and mixed vapors. Inhal Toxicol. 2006 Dec;18(13):1041-6. doi: 10.1080/08958370600904603.
• [19] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [20] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [21] 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.
• [22] 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.
• [23] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [24] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [25] Combined cytotoxicity of phthalate esters on HepG2 cells: A comprehensive analysis of transcriptomics and metabolomics. Food Chem Toxicol. 2023 Oct;180:114034. doi: 10.1016/j.fct.2023.114034. Epub 2023 Sep 12.