Details of Drug Off-Target (DOT)

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

• DOT Name: Flavin-containing monooxygenase 1 (FMO1)
• Synonyms: EC 1.14.13.148; EC 1.14.13.8; Dimethylaniline monooxygenase 1; Dimethylaniline oxidase 1; Fetal hepatic flavin-containing monooxygenase 1; FMO 1; Trimethylamine monooxygenase
• Gene Name: FMO1
• UniProt ID: FMO1_HUMAN
• EC Number: 1.14.13.148; 1.14.13.8
• Pfam ID: PF00743
• Sequence:
  MAKRVAIVGAGVSGLASIKCCLEEGLEPTCFERSDDLGGLWRFTEHVEEGRASLYKSVVS
  NSCKEMSCYSDFPFPEDYPNYVPNSQFLEYLKMYANHFDLLKHIQFKTKVCSVTKCSDSA
  VSGQWEVVTMHEEKQESAIFDAVMVCTGFLTNPYLPLDSFPGINAFKGQYFHSRQYKHPD
  IFKDKRVLVIGMGNSGTDIAVEASHLAEKVFLSTTGGGWVISRIFDSGYPWDMVFMTRFQ
  NMLRNSLPTPIVTWLMERKINNWLNHANYGLIPEDRTQLKEFVLNDELPGRIITGKVFIR
  PSIKEVKENSVIFNNTSKEEPIDIIVFATGYTFAFPFLDESVVKVEDGQASLYKYIFPAH
  LQKPTLAIIGLIKPLGSMIPTGETQARWAVRVLKGVNKLPPPSVMIEEINARKENKPSWF
  GLCYCKALQSDYITYIDELLTYINAKPNLFSMLLTDPHLALTVFFGPCSPYQFRLTGPGK
  WEGARNAIMTQWDRTFKVIKARVVQESPSPFESFLKVFSFLALLVAIFLIFL
• Function: Broad spectrum monooxygenase that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including xenobiotics. Catalyzes the S-oxygenation of hypotaurine to produce taurine, an organic osmolyte involved in cell volume regulation as well as a variety of cytoprotective and developmental processes. In vitro, catalyzes the N-oxygenation of trimethylamine (TMA) to produce trimethylamine N-oxide (TMAO) and could therefore participate to the detoxification of this compound that is generated by the action of gut microbiota from dietary precursors such as choline, choline containing compounds, betaine or L-carnitine.
• Tissue Specificity: Expressed mainly in fetal and adult liver.
• KEGG Pathway:
  Taurine and hypotaurine metabolism (hsa00430)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  FMO oxidises nucleophiles (R-HSA-217271)
  Degradation of cysteine and homocysteine (R-HSA-1614558)
• BioCyc Pathway: MetaCyc:HS00295-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Flavin-containing monooxygenase 1 (FMO1) increases the metabolism of Clozapine.	[14]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methimazole	DM25FL8	Approved	Flavin-containing monooxygenase 1 (FMO1) increases the oxidation of Methimazole.	[15]
Benzydamine	DMEQL9U	Discontinued in Phase 2	Flavin-containing monooxygenase 1 (FMO1) increases the oxidation of Benzydamine.	[16]
Fenthion	DMKEG49	Investigative	Flavin-containing monooxygenase 1 (FMO1) increases the oxidation of Fenthion.	[15]

13 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 Flavin-containing monooxygenase 1 (FMO1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Flavin-containing monooxygenase 1 (FMO1).	[4]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[5]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[6]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[7]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[8]
Atazanavir	DMSYRBX	Approved	Atazanavir decreases the expression of Flavin-containing monooxygenase 1 (FMO1).	[7]
Penicillamine	DM40EF6	Approved	Penicillamine increases the expression of Flavin-containing monooxygenase 1 (FMO1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Flavin-containing monooxygenase 1 (FMO1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Flavin-containing monooxygenase 1 (FMO1).	[12]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Flavin-containing monooxygenase 1 (FMO1).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Flavin-containing monooxygenase 1 (FMO1).	[10]

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] 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] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [6] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [7] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [8] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [9] D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. Apoptosis. 2012 Oct;17(10):1079-94.
• [10] 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.
• [11] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [13] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.
• [14] 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.
• [15] Evaluation of xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Toxicol Sci. 2004 Apr;78(2):196-203.
• [16] Characterization of enzyme activities of Cytochrome P450 enzymes, Flavin-dependent monooxygenases, N-acetyltransferases and UDP-glucuronyltransferases in human reconstructed epidermis and full-thickness skin models. Toxicol In Vitro. 2011 Sep;25(6):1209-14. doi: 10.1016/j.tiv.2011.03.012. Epub 2011 Mar 22.