Carbon tetrachloride at hepatotoxic levels blocks reversibly gap junctions between rat hepatocytes.
Carbon tetrachloride at hepatotoxic levels blocks reversibly gap junctions between rat hepatocytes.
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DOI：
10.1126/science.3576214
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发表时间：
1987-05
期刊：
影响因子：
56.9
通讯作者：
J. Sáez;M. Bennett;D. Spray
中科院分区：
文献类型：
--
作者：
J. Sáez;M. Bennett;D. Spray
通过短暂暴露于卤代甲烷（CBrCl 3，CCl 4和CHCl 3），大鼠肝细胞对之间的电偶联和染料偶联可逆性降低。不同卤代甲烷在解偶联肝细胞中的效力与它们在体内的肝毒性相当，并且等级顺序与它们形成自由基的倾向相同。通过预先使用SKF 525 A（细胞色素P-450抑制剂）处理和暴露于还原剂β-巯基乙醇，四氯化碳（CCl 4）对肝细胞的影响显著降低。卤代甲烷解偶联发生或没有细胞外钙，并没有改变细胞内的钙和氢离子浓度或主要的缝隙连接蛋白的磷酸化状态。因此，解偶联似乎取决于细胞色素P-450的氧化代谢，其中产生自由基，并可能导致间隙连接蛋白或调节分子的氧化，导致间隙连接通道的关闭。连接电导的降低可能是细胞对损伤的快速反应，通过将健康细胞与不健康细胞解偶联来保护健康细胞。
Electrical coupling and dye coupling between pairs of rat hepatocytes were reversibly reduced by brief exposure to halogenated methanes (CBrCl3, CCl4, and CHCl3). The potency of different halomethanes in uncoupling hepatocytes was comparable to their hepatotoxicity in vivo, and the rank order was the same as that of their tendency to form free radicals. The effect of carbon tetrachloride (CCl4) on hepatocytes was substantially reduced by prior treatment with SKF 525A, an inhibitor of cytochrome P-450, and by exposure to the reducing reagent beta-mercaptoethanol. Halomethane uncoupling occurred with or without extracellular calcium and did not change intracellular concentrations of calcium and hydrogen ions or the phosphorylation state of the main gap-junctional protein. Thus the uncoupling appears to depend on cytochrome P-450 oxidative metabolism in which free radicals are generated and may result from oxidation of the gap-junctional protein or of a regulatory molecule that leads to closure of gap-junctional channels. Decreases in junctional conductance may be a rapid cellular response to injury that protects healthy cells by uncoupling them from unhealthy ones.