TitleMammalian flavin-containing monooxygenase (FMO) as a source of hydrogen peroxide.
Publication TypeJournal Article
Year of Publication2014
AuthorsSiddens LK, Krueger SK, Henderson MC, Williams DE
JournalBiochem Pharmacol
Date Published2014 May 01
KeywordsAnimals, Humans, Hydrogen Peroxide, Oxygenases, Sf9 Cells

Flavin-containing monooxygenase (FMO) oxygenates drugs/xenobiotics containing a soft nucleophile through a C4a hydroperoxy-FAD intermediate. Human FMOs 1, 2 and 3, expressed in Sf9 insect microsomes, released 30-50% of O₂ consumed as H₂O₂ upon addition of NADPH. Addition of substrate had little effect on H₂O₂ production. Two common FMO2 (the major isoform in the lung) genetic polymorphisms, S195L and N413K, were examined for generation of H₂O₂. FMO2 S195L exhibited higher "leakage", producing much greater amounts of H₂O₂, than ancestral FMO2 (FMO2.1) or the N413K variant. S195L was distinct in that H₂O₂ generation was much higher in the absence of substrate. Addition of superoxide dismutase did not impact H₂O₂ release. Catalase did not reduce levels of H₂O₂ with either FMO2.1 or FMO3 but inhibited H₂O₂ generated by FMO2 allelic variants N413K and S195L. These data are consistent with FMO molecular models. S195L resides in the GxGxSG/A NADP(+) binding motif, in which serine is highly conserved (76/89 known FMOs). We hypothesize that FMO, especially allelic variants such as FMO2 S195L, may enhance the toxicity of xenobiotics such as thioureas/thiocarbamides both by generation of sulfenic and sulfinic acid metabolites and enhanced release of reactive oxygen species (ROS) in the form of H₂O₂.

Alternate JournalBiochem. Pharmacol.
PubMed ID24561181
PubMed Central IDPMC4116332
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
R01 HL038650 / HL / NHLBI NIH HHS / United States
HL038650 / HL / NHLBI NIH HHS / United States