PHARMACOLOGICAL CORRECTION OF NEONATAL LETHAL HEPATIC-DYSFUNCTION IN A MURINE MODEL OF HEREDITARY TYROSINEMIA TYPE-I
PHARMACOLOGICAL CORRECTION OF NEONATAL LETHAL HEPATIC-DYSFUNCTION IN A MURINE MODEL OF HEREDITARY TYROSINEMIA TYPE-I
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DOI：
10.1038/ng0895-453
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发表时间：
1995-08-01
期刊：
影响因子：
30.8
通讯作者：
FINEGOLD, M
中科院分区：
文献类型：
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作者：
GROMPE, M;LINDSTEDT, S;FINEGOLD, M
I型遗传性酪氨酸血症是一种严重的常染色体隐性代谢疾病，影响肝脏和肾脏，由延胡索酰乙酰乙酸水解酶（FAH）缺乏引起。FAH基因敲除的纯合子小鼠因肝功能障碍具有新生致死表型，不能代表人类该疾病的合适模型。在此我们证明，用2 -（2 - 硝基 - 4 - 三氟甲基苄基）- 1,3 - 环己二酮治疗患病动物可消除新生致死性，纠正肝功能，并使肝脏mRNA的异常表达模式部分恢复正常。患病动物寿命的延长产生了一种类似于人类I型酪氨酸血症的表型，包括肝细胞癌。成年FAH（-/-）小鼠将作为研究I型遗传性酪氨酸血症的病理生理学和治疗以及肝癌的有用模型。
Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH(-/-) mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.