Narasimhan T R, Kim H L, Safe S H
Department of Veterinary Physiology and Pharmacology, Texas A & M University, College Station 77843.
J Biochem Toxicol. 1991 Fall;6(3):229-36. doi: 10.1002/jbt.2570060309.
The effects of three tetrachlorobiphenylols [2',3',4',5'-tetrachloro-2-biphenylol (1); 2',3',4',5'-tetrachloro-4- biphenylol (2); and 2',3',4',5'-tetrachloro-3-biphenylol (3)]; three monochlorobiphenylols [5-chloro-2-biphenylol (5), 3-chloro-2-biphenylol (6); and 2-chloro-4-biphenylol (7)] and a tetrachlorobiphenyldiol [3,3',5,5'-tetrachloro-4,4'-biphenyldiol (4) on respiration, adenosine triphosphatase (ATPase) activity, and swelling in isolated mouse liver mitochondria have been investigated. Tetrachlorobiphenylols (1-3) and the tetrachlorobiphenyldiol (4) inhibited state-3 respiration in a concentration-dependent manner with succinate as substrate (flavin adenine dinucleotide [FAD]-linked) and the tetrachlorobiphenyldiol (4) caused a more pronounced inhibitory effect on state-3 respiration than the other congeners. The monochlorobiphenylols 5-7 were less active as inhibitors of state-3 mitochondrial respiration and significant effects were observed only at higher concentration (greater than or equal to 0.4 microM). However, in the presence of the nicotinamide adenine dinucleotide (NAD)-linked substrates (glutamate plus malate), hydroxylated PCBs (1-7) significantly inhibited mitochondrial state-3 respiration in a concentration-dependent manner. Compounds 5, 6, and 7 uncoupled mitochondrial oxidative phosphorylation only in the presence of FAD-linked substrate as evidenced by increased oxygen consumption during state-4 respiratory transition, stimulating ATPase activity, releasing oligomycin-inhibited respiration, and inducing mitochondrial swelling (5, 6, and 7). Tetrachlorobiphenylols 1, 2, and 3 had no effect on mitochondrial ATPase activity while the tetrachlorobiphenyldiol, 4, decreased the enzyme activity. The possible inhibitory site of electron transport by these compounds and their toxicologic significance is discussed.
研究了三种四氯联苯酚[2',3',4',5'-四氯-2-联苯酚(1);2',3',4',5'-四氯-4-联苯酚(2);和2',3',4',5'-四氯-3-联苯酚(3)]、三种一氯联苯酚[5-氯-2-联苯酚(5)、3-氯-2-联苯酚(6);和2-氯-4-联苯酚(7)]以及一种四氯联苯二醇[3,3',5,5'-四氯-4,4'-联苯二醇(4)]对分离的小鼠肝线粒体呼吸、腺苷三磷酸酶(ATPase)活性和肿胀的影响。以琥珀酸为底物(黄素腺嘌呤二核苷酸[FAD]连接)时，四氯联苯酚(1 - 3)和四氯联苯二醇(4)以浓度依赖的方式抑制状态3呼吸，且四氯联苯二醇(4)对状态3呼吸的抑制作用比其他同系物更明显。一氯联苯酚5 - 7作为状态3线粒体呼吸抑制剂的活性较低，仅在较高浓度(大于或等于0.4 microM)时观察到显著作用。然而，在烟酰胺腺嘌呤二核苷酸(NAD)连接的底物(谷氨酸加苹果酸)存在的情况下，羟基化多氯联苯(1 - 7)以浓度依赖的方式显著抑制线粒体状态3呼吸。化合物5、6和7仅在FAD连接的底物存在时使线粒体氧化磷酸化解偶联，这表现为状态4呼吸转变期间耗氧量增加、刺激ATPase活性、释放寡霉素抑制的呼吸以及诱导线粒体肿胀(5、6和7)。四氯联苯酚1、2和3对线粒体ATPase活性无影响，而四氯联苯二醇4降低了该酶的活性。讨论了这些化合物对电子传递的可能抑制位点及其毒理学意义。
