Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1G2EV3)

• DOT Name: Flavin-containing monooxygenase 3 (FMO3)
• Synonyms: EC 1.14.13.148; EC 1.14.13.32; EC 1.14.13.8; Dimethylaniline monooxygenase 3; Dimethylaniline oxidase 3; FMO II; FMO form 2; Hepatic flavin-containing monooxygenase 3; FMO 3; Trimethylamine monooxygenase
• Gene Name: FMO3
• Related Disease:
  Trimethylaminuria
  Severe primary trimethylaminuria
• UniProt ID: FMO3_HUMAN
• EC Number: 1.14.13.148; 1.14.13.32; 1.14.13.8
• Pfam ID: PF00743
• Sequence:
  MGKKVAIIGAGVSGLASIRSCLEEGLEPTCFEKSNDIGGLWKFSDHAEEGRASIYKSVFS
  NSSKEMMCFPDFPFPDDFPNFMHNSKIQEYIIAFAKEKNLLKYIQFKTFVSSVNKHPDFA
  TTGQWDVTTERDGKKESAVFDAVMVCSGHHVYPNLPKESFPGLNHFKGKCFHSRDYKEPG
  VFNGKRVLVVGLGNSGCDIATELSRTAEQVMISSRSGSWVMSRVWDNGYPWDMLLVTRFG
  TFLKNNLPTAISDWLYVKQMNARFKHENYGLMPLNGVLRKEPVFNDELPASILCGIVSVK
  PNVKEFTETSAIFEDGTIFEGIDCVIFATGYSFAYPFLDESIIKSRNNEIILFKGVFPPL
  LEKSTIAVIGFVQSLGAAIPTVDLQSRWAAQVIKGTCTLPSMEDMMNDINEKMEKKRKWF
  GKSETIQTDYIVYMDELSSFIGAKPNIPWLFLTDPKLAMEVYFGPCSPYQFRLVGPGQWP
  GARNAILTQWDRSLKPMQTRVVGRLQKPCFFFHWLKLFAIPILLIAVFLVLT
• Function: Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds. Plays an important role in the metabolism of trimethylamine (TMA), via the production of trimethylamine N-oxide (TMAO) metabolite. TMA is generated by the action of gut microbiota using dietary precursors such as choline, choline containing compounds, betaine or L-carnitine. By regulating TMAO concentration, FMO3 directly impacts both platelet responsiveness and rate of thrombus formation.
• Tissue Specificity: Liver.
• KEGG Pathway:
  Taurine and hypotaurine metabolism (hsa00430)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective FMO3 causes TMAU (R-HSA-5579019)
  FMO oxidises nucleophiles (R-HSA-217271)
• BioCyc Pathway: MetaCyc:HS00223-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Trimethylaminuria	DIS53PPW	Definitive	Autosomal recessive	[1]
Severe primary trimethylaminuria	DISSFTMR	Strong	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 10 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nicotine	DMWX5CO	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of Nicotine.	[9]
Clozapine	DMFC71L	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of Clozapine.	[10]
Sulindac	DM2QHZU	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of Sulindac.	[11]
Methamphetamine	DMPM4SK	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of Methamphetamine.	[12]
Methimazole	DM25FL8	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of Methimazole.	[14]
Ranitidine	DM0GUSX	Approved	Flavin-containing monooxygenase 3 (FMO3) affects the metabolism of Ranitidine.	[15]
Benzydamine	DMEQL9U	Discontinued in Phase 2	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of Benzydamine.	[18]
Imipramine oxide	DMZKABS	Investigative	Flavin-containing monooxygenase 3 (FMO3) increases the abundance of Imipramine oxide.	[12]
2-(1H-indol-3-yl)-N,N-dimethylethanamine	DMR9Q4Y	Investigative	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of 2-(1H-indol-3-yl)-N,N-dimethylethanamine.	[12]
trimethylamine	DM8LJ3C	Investigative	Flavin-containing monooxygenase 3 (FMO3) increases the metabolism of trimethylamine.	[20]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Docetaxel	DMDI269	Approved	Flavin-containing monooxygenase 3 (FMO3) affects the response to substance of Docetaxel.	[13]
PHENYLTHIOUREA	DMM1IAU	Investigative	Flavin-containing monooxygenase 3 (FMO3) increases the response to substance of PHENYLTHIOUREA.	[19]
Thiourea	DMUELHN	Investigative	Flavin-containing monooxygenase 3 (FMO3) increases the response to substance of Thiourea.	[19]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Almogran	DM7I64Z	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the oxidation of Almogran.	[16]
Perazine	DM2AOTZ	Approved	Flavin-containing monooxygenase 3 (FMO3) increases the oxidation of Perazine.	[17]

2 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 Flavin-containing monooxygenase 3 (FMO3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Flavin-containing monooxygenase 3 (FMO3).	[7]

4 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 Flavin-containing monooxygenase 3 (FMO3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Flavin-containing monooxygenase 3 (FMO3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Flavin-containing monooxygenase 3 (FMO3).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Flavin-containing monooxygenase 3 (FMO3).	[8]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Primary Trimethylaminuria. 2007 Oct 8 [updated 2020 Nov 5]. 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] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] 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.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] Nicotine metabolism, human drug metabolism polymorphisms, and smoking behaviour. Toxicology. 2003 Feb 1;183(1-3):151-73. doi: 10.1016/s0300-483x(02)00513-9.
• [10] Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. Drug Metab Dispos. 2008 Dec;36(12):2547-55. doi: 10.1124/dmd.108.023671. Epub 2008 Sep 22.
• [11] Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis. Clin Cancer Res. 2004 Dec 15;10(24):8357-62. doi: 10.1158/1078-0432.CCR-04-1073.
• [12] What is the contribution of human FMO3 in the N-oxygenation of selected therapeutic drugs and drugs of abuse?. Toxicol Lett. 2016 Sep 6;258:55-70. doi: 10.1016/j.toxlet.2016.06.013. Epub 2016 Jun 15.
• [13] Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS. 2013 Jul;17(7):353-67. doi: 10.1089/omi.2013.0019. Epub 2013 Jun 11.
• [14] Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. J Pharmacol Exp Ther. 2007 Jan;320(1):266-73. doi: 10.1124/jpet.106.112268. Epub 2006 Oct 18.
• [15] Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos. 2004 Nov;32(11):1247-53. doi: 10.1124/dmd.104.000026. Epub 2004 Jul 30.
• [16] Identification of the human liver enzymes involved in the metabolism of the antimigraine agent almotriptan. Drug Metab Dispos. 2003 Apr;31(4):404-11.
• [17] Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro. Psychopharmacology (Berl). 2000 Sep;151(4):312-20.
• [18] Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab Dispos. 2007 Mar;35(3):328-30. doi: 10.1124/dmd.106.013094. Epub 2006 Dec 1.
• [19] Thiourea toxicity in mouse C3H/10T1/2 cells expressing human flavin-dependent monooxygenase 3. Biochem Pharmacol. 2002 Jun 1;63(11):1941-8. doi: 10.1016/s0006-2952(02)00978-4.
• [20] Genetic polymorphisms of flavin-containing monooxygenase (FMO). Drug Metab Rev. 2002 Aug;34(3):523-32. doi: 10.1081/dmr-120005653.