Nishihara Y
Department of Medical Biology, Kochi Medical School, Japan.
Biochem Pharmacol. 1988 Aug 1;37(15):2915-26. doi: 10.1016/0006-2952(88)90276-6.
4-Chlorobiphenyl (4-CB) is converted by the microsomal cytochrome P-450 system to its hydroxylated metabolite 4-chloro-4'-biphenylol (4'-OH-4-CB). A study of the effects of 4-CB and 4'-OH-4-CB on the energy-linked functions of rat liver mitochondria was carried out. 4'-OH-4-CB was more effective than 4-CB in causing the inhibition of state 3 respiration of mitochondria with both succinate and glutamate/malate. As a substrate specificity, with glutamate/malate the inhibition by each compound (ID50, 30 microM for 4'-OH-4-CB, 76 microM for 4.CB) was more significant than that with succinate (ID50, 200 microM for 4'-OH-4-CB, never reached 50% for 4-CB). From the effects on DNP-stimulated respiration, it was indicated that the electron transport from both glutamate/malate and succinate to oxygen was more sensitively inhibited by 4'-OH-4-CB than by 4-CB, with the same substrate specificity as for state 3 respiration (i.e. the inhibition by both compounds was greater with glutamate/malate than with succinate). Since there existed a good coincidence in the inhibition between state 3 and DNP-stimulated respiration with both substrates, the inhibition of state 3 respiration by both compounds was due to the inhibition of the electron transport. With succinate, the uncoupling of oxidative phosphorylation by both compounds was observed, the extent of which was greater with 4'-OH-4-CB than with 4-CB, although the uncoupling by higher concentrations of 4'-OH-4-CB was masked because of the increased inhibition in respiration. With glutamate/malate, the uncoupling action of 4-CB was largely, while that of 4'-OH-4-CB was completely, masked by progressive respiratory inhibition. 4'-OH-4-CB was more effective than 4-CB in causing stimulation of latent ATPase in mitochondria. These results indicate that both 4-CB and 4'-OH-4-CB impair mitochondrial energy-transducing functions, but 4'-OH-4-CB is more effective than 4-CB in damaging these functions. Thus, the product of the metabolism is more biologically active than the parent compound. The impairment of energy-linked mitochondrial reactions by the metabolite as well as of the parent compound may be an important factor in the toxicity of 4-CB.
4-氯联苯（4-CB）经微粒体细胞色素P-450系统转化为其羟基化代谢产物4-氯-4'-联苯酚（4'-OH-4-CB）。开展了一项关于4-CB和4'-OH-4-CB对大鼠肝脏线粒体能量相关功能影响的研究。在琥珀酸以及谷氨酸/苹果酸作为底物时，4'-OH-4-CB比4-CB更能有效抑制线粒体的状态3呼吸。作为底物特异性，对于谷氨酸/苹果酸，每种化合物的抑制作用（4'-OH-4-CB的半数抑制浓度为30微摩尔/升，4-CB为76微摩尔/升）比琥珀酸时更显著（4'-OH-4-CB的半数抑制浓度为200微摩尔/升，4-CB从未达到50%）。从对二硝基苯酚（DNP）刺激呼吸的影响来看，表明从谷氨酸/苹果酸以及琥珀酸到氧的电子传递被4'-OH-4-CB比被4-CB更敏感地抑制，具有与状态3呼吸相同的底物特异性（即两种化合物对谷氨酸/苹果酸的抑制作用比对琥珀酸的更大）。由于在两种底物的状态3和DNP刺激呼吸的抑制之间存在良好的一致性，两种化合物对状态3呼吸的抑制是由于电子传递受到抑制。以琥珀酸为底物时，观察到两种化合物都能使氧化磷酸化解偶联，4'-OH-4-CB的解偶联程度比4-CB更大，尽管由于呼吸抑制增加，高浓度4'-OH-4-CB的解偶联作用被掩盖。以谷氨酸/苹果酸为底物时，4-CB的解偶联作用在很大程度上被逐渐增强的呼吸抑制所掩盖，而4'-OH-4-CB的解偶联作用则完全被掩盖。4'-OH-4-CB比4-CB更能有效刺激线粒体中的潜在ATP酶。这些结果表明，4-CB和4'-OH-4-CB都会损害线粒体的能量转导功能，但4'-OH-4-CB在破坏这些功能方面比4-CB更有效。因此，代谢产物比母体化合物具有更高的生物活性。代谢产物以及母体化合物对能量相关线粒体反应的损害可能是4-CB毒性的一个重要因素。
