Selective alterations in the patterns of newly synthesized proteins by acetaminophen and its dimethylated analogues in primary cultures of mouse hepatocytes.
Selective alterations in the patterns of newly synthesized proteins by acetaminophen and its dimethylated analogues in primary cultures of mouse hepatocytes.
复制标题
对乙酰氨基酚及其二甲基化类似物在小鼠肝细胞原代培养物中选择性改变新合成蛋白质的模式。
DOI：
10.1016/0041-008x(92)90198-2
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发表时间：
1992
影响因子：
3.8
通讯作者：
Khairallah,EA
中科院分区：
文献类型：
--
作者：
Bruno,MK;Cohen,SD;Khairallah,EA
在小鼠肝细胞的原代培养物中研究了接触肝毒性剂量的对乙酰氨基酚 (APAP) 及其类似物 3,5-二甲基对乙酰氨基酚 (3,5-DMA) 和 2,6-二甲基对乙酰氨基酚 (2,6-DMA) 后蛋白质合成的变化。施用 10 mm APAP 后 4 小时内，蛋白质合成速率下降，并且发生在细胞内谷胱甘肽显着耗尽以及 APAP 与蛋白质共价结合之后，但发生在乳酸脱氢酶渗漏到培养基中之前。仅当 APAP 暴露不超过 8 小时时，蛋白质合成的抑制才是可逆的。通过一维SDS-PAGE对35S标记的蛋白质进行电泳分析揭示了新合成蛋白质的模式中的两个一致的改变。首先是迁移大约 58 kDa (p58) 的蛋白质的从头合成逐渐减少。使用 APAP (10 mm) 和 3,5-DMA (5 mm) 观察到这一现象，但使用 2,6-DMA (10 mm) 则没有观察到这一点。如果暴露于APAP超过8小时，这种蛋白质的生物合成不仅进一步减少，而且在恢复期间也不再检测到。第二个主要变化是暴露于 APAP 和 3,5-DMA（但不是 2,6-DMA）并恢复后，32-kDa 蛋白 (p32) 生物合成的相对速率增加。暴露于血红素或亚砷酸盐会诱导相似分子量的蛋白质的合成，但不会导致 p58 生物合成的抑制。 APAP 和 3,5-DMA 的反应性代谢物（而非 2,6-DMA）具有氧化特性，这一事实表明 p32 和 p58 合成的改变可能与这些化合物诱导的氧化成分有关。
Alterations in protein synthesis following exposure to and recovery from hepatotoxic doses of acetaminophen (APAP) and its analogues, 3,5-dimethyl acetaminophen (3,5-DMA) and 2,6-dimethyl acetaminophen (2,6-DMA), were investigated in primary cultures of mouse hepatocytes. The rates of protein synthesis decreased within 4 hr after administration of 10 mm APAP and occurred after significant depletion of intracellular glutathione and covalent binding of APAP to proteins, but preceded the leakage of lactate dehydrogenase into the media. The inhibition of protein synthesis was reversible only if APAP exposure did not exceed 8 hr. Electrophoretic analysis of35S-labeled proteins by one-dimensional SDS-PAGE revealed two consistent alterations in the patterns of newly synthesized proteins. First was a progressive diminution in the de novo synthesis of a protein migrating at approximately 58 kDa (p58). This was observed with APAP (10 mm) and 3,5-DMA (5 mm) but not with 2,6-DMA (10 mm). If exposure to APAP exceeded 8 hr, the biosynthesis of this protein was not only further decreased but was also no longer detectable during the recovery period. The second major alteration was an increase in the relative rate of biosynthesis of a 32-kDa protein (p32) following exposure and recovery from APAP and 3,5-DMA but not 2,6-DMA. Exposure to heme or arsenite induced the synthesis of a protein of similar molecular weight but did not result in the inhibition of p58 biosynthesis. The fact that the reactive metabolites of both APAP and 3,5-DMA, but not 2,6-DMA, possess oxidative properties suggests that the alterations in the synthesis of p32 and p58 may be related to an oxidative component induced by these compounds.