Details of Drug Off-Target (DOT)

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

• DOT Name: Gastrotropin (FABP6)
• Synonyms: GT; Fatty acid-binding protein 6; Ileal lipid-binding protein; ILBP; Intestinal 15 kDa protein; I-15P; Intestinal bile acid-binding protein; I-BABP
• Gene Name: FABP6
• Related Disease:
  Adenoma
  Advanced cancer
  Alzheimer disease
  Barrett esophagus
  Cholelithiasis
  Colonic neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Familial multiple trichoepithelioma
  Non-insulin dependent diabetes
  Colorectal adenocarcinoma
• UniProt ID: FABP6_HUMAN
• PDB ID: 1O1U; 1O1V; 2MM3; 5L8I; 5L8N; 5L8O
• Pfam ID: PF14651
• Sequence:
  MAFTGKFEMESEKNYDEFMKLLGISSDVIEKARNFKIVTEVQQDGQDFTWSQHYSGGHTM
  TNKFTVGKESNIQTMGGKTFKATVQMEGGKLVVNFPNYHQTSEIVGDKLVEVSTIGGVTY
  ERVSKRLA
• Function: Binds to bile acids and is involved in enterohepatic bile acid metabolism. Required for efficient apical to basolateral transport of conjugated bile acids in ileal enterocytes. In vitro binds to bile acids in the order: deoxycholic acid > cholic acid > chenodeoxycholic acid and respective BA conjugation modifies affinities in the order taurine-conjugated > glycine-conjugated > unconjugated bile acids. Stimulates gastric acid and pepsinogen secretion; [Isoform 2]: Essential for the survival of colon cancer cells to bile acid-induced apoptosis.
• Tissue Specificity: Isoform 1 is expressed in the jejunum, ileum, cecum and ascending colon intestine. Isoform 2 is xpressed in the gallbladder, duodenum, jejunum, ileum, cecum, ascending, transverse and descending colon, sigmoid colon and rectum. Isoform 2 is expressed in colorectal adenocarcinomas and their adjacent normal mucosa (at protein level).
• KEGG Pathway: PPAR sig.ling pathway (hsa03320)
• Reactome Pathway:
  Triglyceride catabolism (R-HSA-163560)
  NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis (R-HSA-9623433)
  Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[3]
Cholelithiasis	DISERLZB	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[1]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Colorectal adenocarcinoma	DISPQOUB	Limited	Altered Expression	[8]

17 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 Gastrotropin (FABP6).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gastrotropin (FABP6).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gastrotropin (FABP6).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Gastrotropin (FABP6).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Gastrotropin (FABP6).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Gastrotropin (FABP6).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Gastrotropin (FABP6).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Gastrotropin (FABP6).	[17]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Gastrotropin (FABP6).	[18]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the expression of Gastrotropin (FABP6).	[19]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Gastrotropin (FABP6).	[20]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of Gastrotropin (FABP6).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gastrotropin (FABP6).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Gastrotropin (FABP6).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Gastrotropin (FABP6).	[24]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Gastrotropin (FABP6).	[25]
	DM9CEI5		increases the expression of Gastrotropin (FABP6).	[20]

2 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 Gastrotropin (FABP6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gastrotropin (FABP6).	[22]

References

• [1] Fatty acid binding protein 6 is overexpressed in colorectal cancer.Clin Cancer Res. 2006 Sep 1;12(17):5090-5. doi: 10.1158/1078-0432.CCR-05-2045.
• [2] Increased ileal bile acid binding protein and galectin-9 are associated with mild cognitive impairment and Alzheimer's disease.J Psychiatr Res. 2019 Dec;119:102-106. doi: 10.1016/j.jpsychires.2019.10.002. Epub 2019 Oct 3.
• [3] Expression of bile acid transporting proteins in Barrett's esophagus and esophageal adenocarcinoma.Am J Gastroenterol. 2009 Feb;104(2):302-9. doi: 10.1038/ajg.2008.85. Epub 2009 Jan 27.
• [4] Apical sodium bile acid transporter and ileal lipid binding protein in gallstone carriers.J Lipid Res. 2006 Jan;47(1):42-50. doi: 10.1194/jlr.M500215-JLR200. Epub 2005 Oct 19.
• [5] Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.J Nutr. 2016 Feb;146(2):236-42. doi: 10.3945/jn.115.216580. Epub 2015 Nov 25.
• [6] High expression of FABP4 and FABP6 in patients with colorectal cancer.World J Surg Oncol. 2019 Oct 24;17(1):171. doi: 10.1186/s12957-019-1714-5.
• [7] Evidence for the Thr79Met polymorphism of the ileal fatty acid binding protein (FABP6) to be associated with type 2 diabetes in obese individuals.Mol Genet Metab. 2009 Dec;98(4):400-5. doi: 10.1016/j.ymgme.2009.08.001. Epub 2009 Aug 11.
• [8] A novel variant of ileal bile acid binding protein is up-regulated through nuclear factor-kappaB activation in colorectal adenocarcinoma.Cancer Res. 2007 Oct 1;67(19):9039-46. doi: 10.1158/0008-5472.CAN-06-3690.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [19] Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: role of the farnesoid X receptor. Biochem Pharmacol. 2005 Jun 15;69(12):1755-63. doi: 10.1016/j.bcp.2005.03.019.
• [20] Lithocholic acid decreases expression of UGT2B7 in Caco-2 cells: a potential role for a negative farnesoid X receptor response element. Drug Metab Dispos. 2005 Jul;33(7):937-46.
• [21] Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol Sci. 2012 Apr;126(2):446-56. doi: 10.1093/toxsci/kfs011. Epub 2012 Jan 19.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [25] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.