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Drug Metabolism & Disposition

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OtherShort Communication

Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

Shigeyuki Kitamura, Kayoko Nitta, Yoshitaka Tayama, Chiaki Tanoue, Kazumi Sugihara, Tae Inoue, Toru Horie and Shigeru Ohta
Drug Metabolism and Disposition July 2008, 36 (7) 1202-1205; DOI: https://doi.org/10.1124/dmd.107.019075
Shigeyuki Kitamura
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Kayoko Nitta
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Yoshitaka Tayama
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Chiaki Tanoue
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Kazumi Sugihara
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Tae Inoue
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Toru Horie
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Shigeru Ohta
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Abstract

Aldehyde oxidase-mediated oxidation of N1-methylnicotinamide to N1-methyl-2-pyridine-5-carboxamide (2-PY) and N1-methyl-4-pyridone-5-carboxamide (4-PY) in chimeric mice constructed by transplanting human hepatocytes into urokinase-type plasminogen activator-transgenic severe combined immunodeficient mice was examined in vivo and in vitro. The activity in liver cytosol of chimeric mice with a high replacement index was approximately 4-fold higher than that in control mice. Furthermore, the oxidation products in control mice were 2-PY and 4-PY, whereas, in chimeric mice, the major product was 2-PY, as in humans. The aldehyde oxidase in chimeric mouse liver was confirmed to be of human type by immunoblotting analysis. The ratio of pyridones (2-PY/4-PY) excreted in the urine of chimeric mice was closer to that of humans than to that of control mice. Thus, the aldehyde oxidase in chimeric mice has human-type functional characteristics.

Footnotes

  • This work was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of the Environment and the Japan Society for the Promotion of Science.

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

  • doi:10.1124/dmd.107.019075.

  • ABBREVIATIONS: NMN, N1-methylnicotinamide; 2-PY, N1-methyl-2-pyridone-5-carboxamide; 4-PY, N1-methyl-4-pyridone-3-carboxamide; HPLC, high-performance liquid chromatography; RP value, the ratio of the amounts of pyridones to the total amounts of NMN and pyridones; uPA+/+/SCID, urokinase-type plasminogen activator-transgenic severe combined immunodeficient; RI, replacement index.

    • Received September 30, 2007.
    • Accepted March 5, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (7)
Drug Metabolism and Disposition
Vol. 36, Issue 7
1 Jul 2008
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OtherShort Communication

Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

Shigeyuki Kitamura, Kayoko Nitta, Yoshitaka Tayama, Chiaki Tanoue, Kazumi Sugihara, Tae Inoue, Toru Horie and Shigeru Ohta
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1202-1205; DOI: https://doi.org/10.1124/dmd.107.019075

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OtherShort Communication

Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

Shigeyuki Kitamura, Kayoko Nitta, Yoshitaka Tayama, Chiaki Tanoue, Kazumi Sugihara, Tae Inoue, Toru Horie and Shigeru Ohta
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1202-1205; DOI: https://doi.org/10.1124/dmd.107.019075
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