Shertzer H G, Bannenberg G L, Rundgren M, Moldéus P
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056.
Biochem Pharmacol. 1991 Sep 27;42(8):1587-93. doi: 10.1016/0006-2952(91)90428-8.
In isolated rat hepatocytes, many chemicals elicit toxicity which is inhibitable by antioxidants such as butylated hydroxytoluene (BHT). Although BHT protection is evident at concentrations of less than about 50 nmol/mg protein, higher concentrations exhibit intrinsic concentration-dependent toxicity, which involves mitochondrial dysfunction. We evaluated the possibility that both chemoprotection and intrinsic toxicity could be explained by a common mechanism involving alterations in the physical properties of cellular membranes. In the red blood cell (RBC) osmotic fragility assay, BHT at less than 60 nmol/mg protein protected against osmotic fragility; however, BHT at higher concentrations enhanced osmotic fragility such that total osmolysis occurred at 135 nmol/mg. The BHT-mediated alterations in osmotic fragility correlated with changes in membrane fluidity, determined by fluorescence polarization of the hydrophobic probe 1,6-diphenyl-1,3,5-hexatriene. Protection from osmolysis correlated with decreased fluidity, while enhanced RBC fragility correlated with increased fluidity. In rat hepatocyte suspensions, high BHT concentrations also permeabilized the plasma and mitochondrial membranes to enzyme leakage, and these effects were accompanied by enhanced membrane fluidity. Although other mechanisms may be operative, alterations in membrane fluidity appear to be, in part, responsible for the observed chemoprotective effects at low concentrations, and intrinsic toxicity at higher concentrations of BHT.
在分离的大鼠肝细胞中，许多化学物质会引发毒性，而抗氧化剂如丁基羟基甲苯（BHT）可抑制这种毒性。尽管在浓度低于约50 nmol/mg蛋白质时BHT的保护作用明显，但较高浓度时会表现出内在的浓度依赖性毒性，这涉及线粒体功能障碍。我们评估了化学保护和内在毒性是否都可以用涉及细胞膜物理性质改变的共同机制来解释。在红细胞（RBC）渗透脆性试验中，蛋白质浓度低于60 nmol/mg时BHT可防止渗透脆性；然而，较高浓度的BHT会增强渗透脆性，以至于在135 nmol/mg时发生完全溶血。BHT介导的渗透脆性改变与膜流动性变化相关，膜流动性通过疏水探针1,6 - 二苯基 - 1,3,5 - 己三烯的荧光偏振来测定。防止溶血与流动性降低相关，而增强的红细胞脆性与流动性增加相关。在大鼠肝细胞悬液中，高浓度的BHT也会使质膜和线粒体膜对酶泄漏具有通透性，并且这些效应伴随着膜流动性增强。尽管可能还有其他作用机制，但膜流动性的改变似乎在一定程度上导致了低浓度时观察到的化学保护作用以及高浓度BHT时的内在毒性。
