Nakagawa Y, Moore G
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Biochem Pharmacol. 1999 Sep 1;58(5):811-6. doi: 10.1016/s0006-2952(99)00147-1.
The relationship between mitochondrial membrane permeability transition (MPT) and the toxic effects of the alkyl esters of p-hydroxybenzoic acid (parabens) has been studied in mitochondria and hepatocytes isolated from rat liver. MPT has been proposed as a common final pathway in acute cell death through mitochondrial dysfunction. In isolated mitochondria, propyl-paraben (0.1 to 0.5 mM) in the presence of Ca2+ (50 microM) elicited a concentration-dependent induction of mitochondrial swelling dependent on MPT. This was prevented by pretreatment with a specific inhibitor of MPT, cyclosporin A (0.2 microM). For the other parabens tested, the induction of MPT depended on the relative elongation of alkyl side-chains in their molecular structure and was associated with the partition coefficients. In contrast, the induction caused by p-hydroxybenzoic acid was more potent than that of methyl- or ethyl-paraben. The pretreatment of freshly isolated hepatocytes with cyclosporin A (5 microM) and trifluoperazine (10 microM), which inhibit MPT in a synergistic manner, partially but not completely prevented propyl-paraben (1 mM; plus diazinon, 100 microM)-induced cell death, ATP loss, and decreased mitochondrial membrane potential. These results suggest that the onset of paraben-induced cytotoxicity is linked to mitochondrial failure dependent upon induction of MPT accompanied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation.
对从大鼠肝脏分离出的线粒体和肝细胞，研究了线粒体膜通透性转换（MPT）与对羟基苯甲酸烷基酯（对羟基苯甲酸酯）毒性作用之间的关系。MPT被认为是通过线粒体功能障碍导致急性细胞死亡的常见最终途径。在分离的线粒体中，在Ca2+（50微摩尔）存在的情况下，丙基对羟基苯甲酸酯（0.1至0.5毫摩尔）引发了依赖于MPT的浓度依赖性线粒体肿胀。这可通过用MPT的特异性抑制剂环孢菌素A（0.2微摩尔）预处理来预防。对于测试的其他对羟基苯甲酸酯，MPT的诱导取决于其分子结构中烷基侧链的相对长度，并与分配系数相关。相比之下，对羟基苯甲酸引起的诱导作用比甲基或乙基对羟基苯甲酸酯更强。用环孢菌素A（5微摩尔）和三氟拉嗪（10微摩尔）对新鲜分离的肝细胞进行预处理，它们以协同方式抑制MPT，部分但不完全预防丙基对羟基苯甲酸酯（1毫摩尔；加二嗪农，100微摩尔）诱导的细胞死亡、ATP损失和线粒体膜电位降低。这些结果表明，对羟基苯甲酸酯诱导的细胞毒性的发生与线粒体功能衰竭有关，这依赖于MPT的诱导，伴随着线粒体去极化以及通过氧化磷酸化解偶联导致细胞ATP耗竭。
