Mammalian Flavin-Containing Monooxygenase (FMO) as a Source of Hydrogen Peroxide Public Deposited

http://ir.library.oregonstate.edu/concern/articles/pv63g204c

This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier and can be found at:  http://www.sciencedirect.com/science/journal/00062952.

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  • 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.
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  • Siddens, L. K., Krueger, S. K., Henderson, M. C., & Williams, D. E. (2014). Mammalian flavin-containing monooxygenase (FMO) as a source of hydrogen peroxide. Biochemical Pharmacology, 89(1), 141-147. doi:10.1016/j.bcp.2014.02.006
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  • description.provenance : Submitted by Erin Clark (erin.clark@oregonstate.edu) on 2014-07-11T18:17:48Z No. of bitstreams: 2 SiddensLisbethEnvMolecularToxicMammalianFlavin-Containing.pdf: 331183 bytes, checksum: 62fcd4dfccdb665ce634b51cc3202564 (MD5) SiddensLisbethEnvMolecularToxicMammalianFlavin-Containing_Figures1-9.zip: 1907752 bytes, checksum: 207af579ede3878f96743ef3ef977d09 (MD5)
  • description.provenance : Made available in DSpace on 2014-07-11T18:18:03Z (GMT). No. of bitstreams: 2 SiddensLisbethEnvMolecularToxicMammalianFlavin-Containing.pdf: 331183 bytes, checksum: 62fcd4dfccdb665ce634b51cc3202564 (MD5) SiddensLisbethEnvMolecularToxicMammalianFlavin-Containing_Figures1-9.zip: 1907752 bytes, checksum: 207af579ede3878f96743ef3ef977d09 (MD5) Previous issue date: 2014-05-01
  • description.provenance : Approved for entry into archive by Erin Clark(erin.clark@oregonstate.edu) on 2014-07-11T18:18:03Z (GMT) No. of bitstreams: 2 SiddensLisbethEnvMolecularToxicMammalianFlavin-Containing.pdf: 331183 bytes, checksum: 62fcd4dfccdb665ce634b51cc3202564 (MD5) SiddensLisbethEnvMolecularToxicMammalianFlavin-Containing_Figures1-9.zip: 1907752 bytes, checksum: 207af579ede3878f96743ef3ef977d09 (MD5)

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