Aldehyde oxidase-catalyzed metabolism of N1-methylnicotinamide in vivo and in vitro in chimeric mice with humanized liver.
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.
Kitamura
Shigeyuki
S
Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan. skitamu@hiroshima-u.ac.jp
Nitta
Kayoko
K
Tayama
Yoshitaka
Y
Tanoue
Chiaki
C
Sugihara
Kazumi
K
Inoue
Tae
T
Horie
Toru
T
Ohta
Shigeru
S
D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002678:Chimera; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism
D009536:Niacinamide; D042931:Aldehyde Oxidase; C024058:N(1)-methylnicotinamide