Susceptibility to Hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant
Susceptibility to Hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant
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DOI：
10.1172/jci118864
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发表时间：
1996-08-15
影响因子：
15.9
通讯作者：
Omary, MB
中科院分区：
文献类型：
--
作者：
Ku, NO;Michie, SA;Omary, MB
角蛋白8和18（K8/18）是一种优先在单纯型上皮细胞中表达的中间丝磷酸糖蛋白。我们最近描述了表达点突变的人K18的转基因小鼠（Ku，N.- O.，S. R.G.米吉Oshima和M.B.奥玛丽1995. J. Cell Biol.131：1303-1314）并发展与肝细胞角蛋白丝破坏相关的慢性肝炎和肝细胞脆性。在此，我们表明表达突变K18的转基因小鼠在急性施用对乙酰氨基酚（400 mg/Kg）或慢性摄入灰黄霉素（饮食的1.25%wt/wt）后对肝毒性高度敏感。肝毒性的倾向直接由角蛋白突变引起，因为表达正常人K18的非转基因或转基因小鼠更具抗性。在所有灰黄霉素喂养的小鼠中，角蛋白糖基化降低，而角蛋白磷酸化在表达正常K18的小鼠中显著优先增加。灰黄霉素喂养后正常K18中磷酸化的增加似乎涉及与部分肝切除术后增加的那些不同的位点。我们的结果表明，肝细胞中间丝破坏使小鼠对肝毒性高度敏感，并提出了K18突变可能导致药物肝毒性的可能性。非突变角蛋白磷酸化的显著增加可能为肝细胞提供生存优势。
Keratins 8 and 18 (K8/18) are intermediate filament phosphoglycoproteins that are expressed preferentially in simple-type epithelia. We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary. 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption, Here we show that mutant K18 expressing transgenic mice are highly susceptible to hepatotoxicity after acute administration of acetaminophen (400 mg/Kg) or chronic ingestion of griseofulvin (1.25% wt/wt of diet), The predisposition to hepatotoxicity results directly from the keratin mutation since nontransgenic or transgenic mice that express normal human K18 are more resistant, Hepatotoxicity was manifested by a significant difference in lethality, liver histopathology, and biochemical serum testing. Keratin glycosylation decreased in all griseofulvin-fed mice, whereas keratin phosphorylation increased dramatically preferentially in mice expressing normal K18, The phosphorylation increase in normal K18 after griseofulvin feeding appears to involve sites that are different to those that increase after partial hepatectomy, Our results indicate that hepatocyte intermediate filament disruption renders mice highly susceptible to hepatotoxicity, and raises the possibility that K18 mutations may predispose to drug hepatotoxicity. The dramatic phosphorylation increase in nonmutant keratins could provide survival advantage to hepatocytes.