The concentration and temporal relationships of acetaminophen-induced changes in intracellular and extracellular total glutathione in freshly isolated hepatocytes from untreated and 3-methylcholanthrene pretreated Sprague-Dawley and Fischer rats.
The concentration and temporal relationships of acetaminophen-induced changes in intracellular and extracellular total glutathione in freshly isolated hepatocytes from untreated and 3-methylcholanthrene pretreated Sprague-Dawley and Fischer rats.
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未经处理和 3-甲基胆蒽预处理的 Sprague-Dawley 和 Fischer 大鼠新鲜分离的肝细胞中对乙酰氨基酚诱导的细胞内和细胞外总谷胱甘肽变化的浓度和时间关系。
DOI：
10.1111/j.1600-0773.1991.tb01298.x
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Hall,T
中科院分区：
文献类型：
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作者：
Willson,RA;Hart,J;Hall,T
Fischer大鼠对对乙酰氨基酚诱导的肝毒性比Sprague - Dawley大鼠更敏感，然而，这种增强敏感性的机制尚不清楚。肝毒性的易感性主要取决于对乙酰氨基酚中毒和解毒之间的平衡。由于谷胱甘肽在解毒过程中起着至关重要的作用，比较对乙酰氨基酚对Sprague - Dawley和Fischer大鼠肝脏谷胱甘肽稳态的影响，并将这些影响与细胞毒性联系起来，将是一项有趣的研究。为此，我们测量了未经处理和3 -甲基蒽预处理的Fischer和Sprague - Dawley大鼠新鲜分离的肝细胞中细胞内和细胞外总谷胱甘肽的顺序变化，无论是在缺乏（基础）和存在对乙酰氨基酚的情况下。在基础状态下，未经处理的Fischer大鼠肝细胞内总谷胱甘肽含量显著（P < 0.01）升高。然而，在未经治疗的Fischer和Sprague - Dawley大鼠肝细胞中，总谷胱甘肽在培养基中的顺序释放和细胞内总谷胱甘肽的顺序消耗在数量上是相似的。暴露于对乙酰氨基酚后，两种大鼠菌株未经处理的肝细胞中细胞内总谷胱甘肽的消耗与剂量和时间相关，并且在数量上，两种大鼠菌株未经处理的肝细胞的消耗相似。在Sprague - Dawley肝细胞中，细胞内总谷胱甘肽的这种消耗程度与对乙酰氨基酚诱导的细胞毒性无关，而在Fischer肝细胞中则显示出显著的（P < 0.05）细胞毒性。在3‐甲基胆蒽预处理的大鼠肝细胞中，与未处理的两种大鼠肝细胞相比，细胞内总谷胱甘肽的剂量和时间相关耗竭更为明显。尽管对乙酰氨基酚在两种大鼠肝细胞中的毒性减弱程度相似，但对乙酰氨基酚诱导的细胞毒性在Fischer大鼠肝细胞中更为显著（P < 0.01）。我们的观察证实Fischer大鼠的基础肝细胞谷胱甘肽浓度高于Sprague - Dawley大鼠，然而两种菌株肝细胞中基础细胞内和细胞外谷胱甘肽的顺序变化是相似的。此外，对乙酰氨基酚对这两种大鼠肝细胞中谷胱甘肽的影响也是相似的。最后，我们的观察揭示了两种大鼠菌株中对乙酰氨基酚诱导的细胞毒性和细胞谷胱甘肽含量之间的不一致，这意味着Fischer大鼠对肝细胞损伤的易感性增强可能与对乙酰氨基酚反应性代谢物攻击的固有细胞防御机制缺陷有关。
Fischer rats are more sensitive to acetaminophen‐induced hepatotoxicity than Sprague‐Dawley rats, however, the mechanisms for this enhanced sensitivity remain unclear. The susceptability to hepatotoxicity is determined largely by the balance between acetaminophen toxification and detoxification. Since glutathione plays a critical role in the detoxification process, it would be of interest to compare the effects of acetaminophen on hepatic glutathione homeostasis in the Sprague‐Dawley and Fischer rat, and relate these effects to cytotoxicity. To this end, we measured the sequential changes of intracellular and extracellular total glutathione in freshly isolated hepatocytes from untreated and 3‐methylchol‐anthrene pretreated Fischer and Sprague‐Dawley rats, both in the absence (basal) and presence of acetaminophen. In the basal state, the intracellular total glutathione content was significantly (P < 0.01) increased in hepatocytes from untreated Fischer rats. Nevertheless, the sequential release of total glutathione into the medium and the sequential depletion of intracellular total glutathione were quantitatively similar in hepatocytes from untreated Fischer and Sprague‐Dawley rats. Following exposure to acetaminophen, there was a striking dose and time associated depletion of intracellular total glutathione in untreated hepatocytes from both rat strains, and quantitatively the depletion was similar in untreated hepatocytes from both rat strains. This degree of depletion of intracellular total glutathione was not associated with acetaminophen‐induced cytotoxicity in Sprague‐Dawley hepatocytes, whereas significant (P < 0.05) cytotoxicity was demonstrated in Fischer hepatocytes. In hepatocytes from 3‐methylcholanthrene pretreated rats, there was an even more marked dose and time associated depletion of intracellular total glutathione as compared with untreated hepatocytes from both rat strains. Although the magnitude of this depletion was also similar in hepatocytes from both rat strains, the acetaminophen‐induced cytotoxicity was significantly (P < 0.01) more prominent in hepatocytes from the Fischer rat. Our observations establish that basal hepatocellular glutathione concentrations are higher in Fischer than Sprague‐Dawley rats, however sequential changes in basal intracellular and extracellular glutathione are similar in hepatocytes of both strains. Moreover, the effect of acetaminophen on these glutathione measures was also similar in hepatocytes from both rat strains. Finally, our observations reveal a discordance between acetaminophen‐induced cytotoxicity and cellular glutathione content in the two rat strains, implying that the Fischer rats'enhanced susceptibility to hepatocellular injury may be related to a defective inherent cellular defense mechanism against attack by the reactive metabolite of acetaminophen.