Nakagawa Y, Tayama S, Moore G, Moldéus P
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Biochem Pharmacol. 1993 May 25;45(10):1959-65. doi: 10.1016/0006-2952(93)90004-g.
The cytotoxic effects of biphenyl (BP) and its hydroxylated derivatives, o-phenylphenol (OPP), m-phenylphenol (MPP), p-phenylphenol (PPP), 2-biphenylyl glycidyl ether (OPP-epoxide), phenyl-hydroquinone (PHQ), o,o'-biphenol (o,o'-BPol) and p,p'-biphenol (p,p'-BPol), were investigated in freshly isolated rat hepatocytes. OPP, MPP and PPP, at concentration of 0.75 mM, resulted in the loss of intracellular ATP, glutathione (GSH) and protein thiols, causing cell death. OPP-epoxide and BP were less toxic than the OPP isomers. MPP or PPP compared with OPP caused serious impairments in oxidative phosphorylation in mitochondria isolated from rat liver. PHQ (0.75 mM) caused a rapid loss of intracellular ATP which preceded the onset of cell death. PHQ was more toxic than o,o'-BPol or p,p'-BPol. PHQ dissolved in Krebs-Henseleit buffer without hepatocytes was rapidly converted to its corresponding quinone, phenyl-benzoquinone. The cytotoxicity produced by PHQ depends on the rate of formation of reactive intermediates. These results indicate that the addition of a hydroxyl group to the aromatic ring of BP enhances BP-induced cytotoxicity and that the mitochondria are a common target of the OPP isomers and other BP derivatives. In addition, the para- or meta-hydroxyl groups rather than the ortho-hydroxyl group increase the toxicity. The cytotoxicity produced by PHQ depends on the rate of formation of reactive intermediate(s) such as phenyl-benzoquinone.
在新鲜分离的大鼠肝细胞中研究了联苯（BP）及其羟基化衍生物邻苯基苯酚（OPP）、间苯基苯酚（MPP）、对苯基苯酚（PPP）、2-联苯基缩水甘油醚（OPP-环氧化物）、苯基对苯二酚（PHQ）、邻，邻'-联苯酚（o，o'-BPol）和对，对'-联苯酚（p，p'-BPol）的细胞毒性作用。浓度为0.75 mM的OPP、MPP和PPP导致细胞内ATP、谷胱甘肽（GSH）和蛋白质巯基的损失，从而导致细胞死亡。OPP-环氧化物和BP的毒性低于OPP异构体。与OPP相比，MPP或PPP对从大鼠肝脏分离的线粒体中的氧化磷酸化造成严重损害。PHQ（0.75 mM）导致细胞内ATP迅速损失，这发生在细胞死亡开始之前。PHQ比o，o'-BPol或p，p'-BPol毒性更大。溶解在不含肝细胞的Krebs-Henseleit缓冲液中的PHQ迅速转化为其相应的醌，即苯基苯醌。PHQ产生的细胞毒性取决于反应性中间体的形成速率。这些结果表明，在BP的芳环上添加羟基会增强BP诱导的细胞毒性，并且线粒体是OPP异构体和其他BP衍生物的共同靶点。此外，对羟基或间羟基而非邻羟基会增加毒性。PHQ产生的细胞毒性取决于反应性中间体如苯基苯醌的形成速率。
