Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice.
Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice.
复制标题
对 Hsp70i 敲除小鼠中对乙酰氨基酚的肝毒性增加。
DOI：
10.1016/j.taap.2005.10.001
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发表时间：
2006
影响因子：
3.8
通讯作者：
Roberts,StephenM
中科院分区：
文献类型：
--
作者：
Tolson,JKeith;Dix,DavidJ;Voellmy,RichardW;Roberts,StephenM
在Hsp 70 i基因敲除小鼠模型中评估了诱导形式的70 kDa热休克蛋白（Hsp 70 i）对对乙酰氨基酚（APAP）肝毒性的影响。通过监测热应激（41.5 °C水浴浸泡30分钟）后敲除小鼠和对照小鼠中的Hsp水平来验证肝脏中Hsp 70 i蛋白的不存在。Hsp 70 i基因敲除小鼠比对照组更容易受到APAP诱导的肝毒性，如APAP剂量后24和48小时血清丙氨酸氨基转移酶活性升高所示。通过肝脏切片的形态学评价证实了敲除小鼠中APAP肝毒性增加。敲除和对照品系小鼠对APAP毒性反应的差异不能归因于APAP生物活化的差异，通过测量CYP 2 E1和谷胱甘肽S-转移酶活性、肝脏非蛋白巯基含量或反应性APAP代谢产物与蛋白质的共价结合来评估。用瞬时高温预处理以产生Hsps的普遍上调，导致敲除和对照菌株中APAP肝毒性降低。在热预处理的小鼠中，与对照菌株相比，APAP的肝毒性在敲除中更大。这些观察结果表明，响应于APAP的增加的Hsp 70 i表达起到限制组织损伤的程度的作用。结果进一步表明，与热应激相关的其他因素也有助于防止APAP毒性。
The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 °C water bath immersion for 30 min). Hsp70i knockout mice were more susceptible to APAP-induced hepatotoxicity than controls, as indicated by elevated serum alanine aminotransferase activities 24 and 48 h after the APAP dose. Increased APAP hepatotoxicity in knockout mice was verified by morphological evaluation of liver sections. The difference in toxic response to APAP between knockout and control strain mice could not be attributed to differences in APAP bioactivation, assessed by measurement of CYP2E1 and glutathione S-transferase activities, hepatic nonprotein sulfhydryl content, or covalent binding of reactive APAP metabolites to proteins. Pretreatment with transient hyperthermia to produce a general upregulation of Hsps resulted in decreased APAP hepatotoxicity in both the knockout and control strains. Among thermally-pretreated mice, hepatotoxicity of APAP was greater in the knockouts compared with the control strain. These observations suggest that increased Hsp70i expression in response to APAP acts to limit the extent of tissue injury. Results further suggest that other factors related to heat stress can also contribute to protection against APAP toxicity.