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Effect of Genetic Variants of the Human Flavin-Containing Monooxygenase 3 on N- and S-Oxygenation Activities

Makiko Shimizu, Hiroshi Yano, Satomi Nagashima, Norie Murayama, Jun Zhang, John R. Cashman and Hiroshi Yamazaki
Drug Metabolism and Disposition March 2007, 35 (3) 328-330; DOI: https://doi.org/10.1124/dmd.106.013094
Makiko Shimizu
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Hiroshi Yano
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Satomi Nagashima
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Norie Murayama
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Jun Zhang
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John R. Cashman
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Hiroshi Yamazaki
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Abstract

The decreased capacity of the flavin-containing monooxygenase 3 (FMO3) to oxygenate xenobiotics including trimethylamine is believed to contribute to metabolic disorders. The aim of this study was to functionally characterize FMO3 variants recently found in a Japanese population and compare them with selective functional activity of other FMO3 variants. Recombinant Glu158Lys and Glu158Lys-Glu308Gly FMO3 expressed in Escherichia coli membranes showed slightly decreased N-oxygenation of benzydamine and trimethylamine. Selective functional S-oxygenation of these variants by methyl p-tolyl sulfide or sulindac sulfide was comparable to that of wild-type FMO3. The Glu158Lys-Thr201Lys-Glu308Gly and Val257Met-Met260Val variants showed significantly decreased oxygenation of typical FMO3 substrates (i.e., approximately one-tenth of the Vmax/Km values). Val257Met FMO3 had a lower catalytic efficiency for methyl p-tolyl sulfide and sulindac sulfide S-oxygenation. However, compared with wild-type FMO3, Val257Met FMO3 showed a similar catalytic efficiency for N-oxygenation of benzydamine and trimethylamine. The catalytic efficiency for benzydamine and trimethylamine N-oxygenation by Arg205Cys FMO3 was only moderately decreased, but it possessed decreased sulindac sulfide S-oxygenation activity. Kinetic analysis showed that Arg205Cys FMO3 was inhibited by sulindac in a substrate-dependent manner, presumably because of selective interaction between the variant enzyme and the substrate. The results suggest that the effects of genetic variation of human FMO3 could operate at the functional level for N- and S-oxygenation for typical FMO3 substrates. Genetic polymorphism in the human FMO3 gene might lead to unexpected changes of catalytic efficiency for N- and S-oxygenation of xenobiotics and endogenous materials.

Footnotes

  • This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan and Japan Research Foundation for Clinical Pharmacology. J.R.C. was supported financially by a grant from the National Institutes of Health (Grant DK 59618).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.013094.

  • ABBREVIATIONS: FMO, flavin-containing monooxygenase; HPLC, high-performance liquid chromatography.

    • Received September 22, 2006.
    • Accepted November 29, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (3)
Drug Metabolism and Disposition
Vol. 35, Issue 3
1 Mar 2007
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OtherShort Communication

Effect of Genetic Variants of the Human Flavin-Containing Monooxygenase 3 on N- and S-Oxygenation Activities

Makiko Shimizu, Hiroshi Yano, Satomi Nagashima, Norie Murayama, Jun Zhang, John R. Cashman and Hiroshi Yamazaki
Drug Metabolism and Disposition March 1, 2007, 35 (3) 328-330; DOI: https://doi.org/10.1124/dmd.106.013094

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OtherShort Communication

Effect of Genetic Variants of the Human Flavin-Containing Monooxygenase 3 on N- and S-Oxygenation Activities

Makiko Shimizu, Hiroshi Yano, Satomi Nagashima, Norie Murayama, Jun Zhang, John R. Cashman and Hiroshi Yamazaki
Drug Metabolism and Disposition March 1, 2007, 35 (3) 328-330; DOI: https://doi.org/10.1124/dmd.106.013094
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