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Aldehyde Oxidase-Catalyzed Metabolism of N 1 -Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

2008; American Society for Pharmacology and Experimental Therapeutics; Volume: 36; Issue: 7 Linguagem: Inglês

10.1124/dmd.107.019075

1521-009X

Shigeyuki Kitamura, Kayoko Nitta, Yoshitaka Tayama, Chiaki Tanoue, Kazumi Sugihara, Tae Inoue, Toru Horie, Shigeru Ohta,

Pharmacological Effects of Natural Compounds

Aldehyde oxidase-mediated oxidation of N 1 -methylnicotinamide to N 1 -methyl-2-pyridine-5-carboxamide (2-PY) and N 1 -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.