Aldehyde oxidase-catalyzed metabolism of N1-methylnicotinamide in vivo and in vitro in chimeric mice with humanized liver
Aldehyde oxidase-catalyzed metabolism of N1-methylnicotinamide in vivo and in vitro in chimeric mice with humanized liver
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DOI：
10.1124/dmd.107.019075
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发表时间：
2008-07-01
影响因子：
3.9
通讯作者：
Ohta, Shigeru
中科院分区：
文献类型：
--
作者：
Kitamura, Shigeyuki;Nitta, Kayoko;Ohta, Shigeru
在体内和体外研究了将人肝细胞移植到转尿激酶型纤溶酶原激活剂的重度联合免疫缺陷小鼠体内构建的嵌合小鼠中，醛氧化酶介导的n -1-甲基烟酰胺氧化为n -1-甲基-2-吡啶-5-羧酰胺（2-PY）和n -1-甲基-4-吡啶-5-羧酰胺（4-PY）。高替代指数嵌合小鼠的肝细胞质活性约为对照小鼠的4倍。此外，对照小鼠的氧化产物是2-PY和4-PY，而嵌合小鼠的主要产物是2-PY，与人类一样。免疫印迹分析证实，嵌合小鼠肝脏中的醛氧化酶为人型。嵌合小鼠尿液中吡啶酮的排泄比（2-PY/4-PY）更接近人类，而非对照小鼠。因此，嵌合小鼠的醛氧化酶具有人型的功能特征。
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.