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Biochem Pharmacol. 2014 May 1;89(1):141-7. doi: 10.1016/j.bcp.2014.02.006. Epub 2014 Feb 19.

Mammalian flavin-containing monooxygenase (FMO) as a source of hydrogen peroxide.

Author information

1
Department of Environmental and Molecular Toxicology, USA. Electronic address: siddensb@onid.oregonstate.edu.
2
The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. Electronic address: sharon.krueger@oregonstate.edu.
3
Department of Environmental and Molecular Toxicology, USA. Electronic address: marilyn.henderson@comcast.net.
4
Department of Environmental and Molecular Toxicology, USA; The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. Electronic address: david.williams@oregonstate.edu.

Abstract

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.

KEYWORDS:

Flavin-containing monooxygenase; Genetic polymorphism; Hydrogen peroxide; Oxidative stress; Pulmonary FMO2

PMID:
24561181
PMCID:
PMC4116332
DOI:
10.1016/j.bcp.2014.02.006
[Indexed for MEDLINE]
Free PMC Article

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