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
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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.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019075.
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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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