Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9DX3N1)

• DOT Name: Fatty-acid amide hydrolase 1 (FAAH)
• Synonyms: EC 3.5.1.99; Anandamide amidohydrolase 1; Fatty acid ester hydrolase; EC 3.1.1.-; Oleamide hydrolase 1
• Gene Name: FAAH
• UniProt ID: FAAH1_HUMAN
• EC Number: 3.1.1.-; 3.5.1.99
• Pfam ID: PF01425
• Sequence:
  MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRAGLENMDRAAQ
  RFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNCVTSYLAD
  CETQLSQAPRQGLLYGVPVSLKECFTYKGQDSTLGLSLNEGVPAECDSVVVHVLKLQGAV
  PFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGG
  SIRFPSSFCGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALLCE
  DMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETKQSLEAAGHTL
  VPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPCLGDLVSILKLPQWLKGLLAF
  LVKPLLPRLSAFLSNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDVVLTPMLAPALD
  LNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMK
  KSVGLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS
• Function: Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates. It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol). FAAH cooperates with PM20D1 in the hydrolysis of amino acid-conjugated fatty acids such as N-fatty acyl glycine and N-fatty acyl-L-serine, thereby acting as a physiological regulator of specific subsets of intracellular, but not of extracellular, N-fatty acyl amino acids.
• Tissue Specificity: Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate.
• KEGG Pathway: Retrograde endocan.binoid sig.ling (hsa04723)
• Reactome Pathway: Arachidonic acid metabolism (R-HSA-2142753)
• BioCyc Pathway: MetaCyc:HS04139-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Amphetamine	DMSZQAK	Approved	Fatty-acid amide hydrolase 1 (FAAH) affects the response to substance of Amphetamine.	[16]

14 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 Fatty-acid amide hydrolase 1 (FAAH).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[2]
Marinol	DM70IK5	Approved	Marinol affects the expression of Fatty-acid amide hydrolase 1 (FAAH).	[4]
Selenium	DM25CGV	Approved	Selenium increases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[7]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[8]
ASP-8477	DMBZQS7	Phase 2	ASP-8477 decreases the activity of Fatty-acid amide hydrolase 1 (FAAH).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fatty-acid amide hydrolase 1 (FAAH).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the activity of Fatty-acid amide hydrolase 1 (FAAH).	[12]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon decreases the activity of Fatty-acid amide hydrolase 1 (FAAH).	[13]
Org-231295	DMTFGYH	Investigative	Org-231295 decreases the activity of Fatty-acid amide hydrolase 1 (FAAH).	[14]
RHC80267	DMC471Z	Investigative	RHC80267 decreases the activity of Fatty-acid amide hydrolase 1 (FAAH).	[15]

1 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 Fatty-acid amide hydrolase 1 (FAAH).	[3]

References

• [1] 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.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] 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.
• [4] Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta. Arch Toxicol. 2019 Mar;93(3):649-658. doi: 10.1007/s00204-019-02389-7. Epub 2019 Jan 18.
• [5] 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.
• [6] Further insights into the regulation of human FAAH by progesterone and leptin implications for endogenous levels of anandamide and apoptosis of immune and neuronal cells. Neurotoxicology. 2005 Oct;26(5):811-7.
• [7] Cannabidiol regulates CB1-pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of A pathology models. FASEB J. 2021 May;35(5):e21537. doi: 10.1096/fj.202002724R.
• [8] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [9] In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor. Eur J Pharmacol. 2017 Nov 15;815:42-48. doi: 10.1016/j.ejphar.2017.10.007. Epub 2017 Oct 7.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] 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.
• [12] Bisphenol A induces fatty liver by an endocannabinoid-mediated positive feedback loop. Endocrinology. 2016 May;157(5):1751-63.
• [13] Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells. Toxicol In Vitro. 2022 Feb;78:105268. doi: 10.1016/j.tiv.2021.105268. Epub 2021 Oct 29.
• [14] Parabens inhibit fatty acid amide hydrolase: a potential role in paraben-enhanced 3T3-L1 adipocyte differentiation. Toxicol Lett. 2016 Nov 16;262:92-99.
• [15] Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41.
• [16] More aroused, less fatigued: fatty acid amide hydrolase gene polymorphisms influence acute response to amphetamine. Neuropsychopharmacology. 2010 Feb;35(3):613-22. doi: 10.1038/npp.2009.166. Epub 2009 Nov 4.