Protection against acetaminophen hepatotoxicity by a single dose of clofibrate: Effects on selective protein arylation and glutathione depletion
Protection against acetaminophen hepatotoxicity by a single dose of clofibrate: Effects on selective protein arylation and glutathione depletion
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DOI：
10.1006/faat.1996.0026
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发表时间：
1996-02-01
期刊：
影响因子：
--
通讯作者：
Cohen, SD
中科院分区：
文献类型：
--
作者：
Manautou, JE;Hart, SGE;Cohen, SD
先前的报告表明，重复给药过氧化物酶体增殖剂可以防止小鼠对乙酰氨基酚（APAP）肝毒性。这种保护作用与APAP选择性蛋白芳基化和谷胱甘肽耗竭的减少有关。本研究旨在确定单剂量氯贝特（CFB）是否与重复剂量相比，同样可以预防APAP毒性。CD-1雄性小鼠在APAP攻击前24小时给予单剂量500 mg CFB/kg，对照组给予玉米油。禁食18小时后，用800 mg APAP/kg（50%丙二醇）刺激小鼠，在4或12小时杀死小鼠。其他经过类似预处理的小鼠在没有APAP刺激的情况下被杀死。结果表明，单剂量CFB预处理可显著降低apap诱导的肝毒性。在APAP作用12小时后，经CFB预处理的小鼠血浆山梨醇脱氢酶活性和肝细胞坏死严重程度均有所降低。令人惊讶的是，在APAP攻击后4小时，肝非蛋白巯基（NPSH）的消耗或细胞质中靶蛋白的选择性芳基化没有观察到差异。在APAP攻击前，单剂量CFB也没有显著改变肝脏NPSH含量。这些结果表明，CFB对APAP肝毒性的保护不需要重复给药，而且APAP的选择性蛋白芳基化或谷胱甘肽缺失没有显著改变，这表明单次CFB治疗对APAP肝毒性的保护可能与重复给药后观察到的保护在机制上有所不同。(C) 1996年毒理学学会
Previous reports demonstrated that repeated administration of peroxisome proliferators protects against acetaminophen (APAP) hepatotoxicity in mice. This protection was associated with a decrease in APAP's selective protein arylation and glutathione depletion. This study was conducted to determine if a single dose of clofibrate (CFB), rather than repeated doses, would similarly prevent APAP toxicity. CD-1 male mice received a single dose of 500 mg CFB/kg and controls were given corn oil 24 hr prior to APAP challenge. After an 18-hr fast, mice were challenged with 800 mg APAP/kg (in 50% propylene glycol) and killed at 4 or 12 hr. Other mice similarly pretreated were killed without APAP challenge. The results showed that pretreatment with a single CFB dose significantly decreased APAP-induced hepatotoxicity. At 12 hr after APAP plasma sorbitol dehydrogenase activity and the severity of hepatocellular necrosis were decreased in CFB pretreated mice. Surprisingly, no differences in hepatic nonprotein sulfhydryl (NPSH) depletion or selective arylation of target proteins in cytosol were observed at 4 hr after APAP challenge. Neither did a single dose of CFB significantly alter hepatic NPSH content prior to APAP challenge. These results indicate that protection against APAP hepatotoxicity by CFB does not require repeated administration, and the absence of significant alterations in APAP's selective protein arylation or glutathione depletion suggests that the protection against APAP hepatotoxicity after a single treatment with CFB may differ mechanistically from the protection observed after repeated CFB dosing. (C) 1996 Society of Toxicology