Several nongenotoxic carcinogens uncouple mitochondrial oxidative phosphorylation.
Several nongenotoxic carcinogens uncouple mitochondrial oxidative phosphorylation.
复制标题
几种非基因毒性致癌物会解开线粒体氧化磷酸化。
DOI：
10.1016/0005-2728(92)90105-b
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Thurman,RG
中科院分区：
文献类型：
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作者：
Keller,BJ;Marsman,DS;Popp,JA;Thurman,RG
许多增塑剂和降脂药物诱导过氧化物酶体，并导致啮齿动物肝细胞癌的机制仍然未知。在这项研究中，七种结构不同的过氧化物酶体增殖剂被证明在离体大鼠肝线粒体中解偶联氧化磷酸化。例如，全氟辛酸盐（0.5mM）使琥珀酸盐诱导的（状态4）线粒体呼吸增加超过50%，而ADP对状态3呼吸的刺激最小（即，发生解偶联）。有趣的是，在体内是有效致癌物的化合物（例如Wy-14.643和全氟辛酸酯）在体外是比弱致肿瘤剂（例如，丙戊酸盐）。解偶联也发生在体内。喂食Wy-14.643（饲料中0.1% w/v）2.5个月后，长期给药大鼠灌注肝脏的基础摄氧量从配对喂养对照组的137 ± 7 μmol g1/h增加至153 ± 5 μmol g1/h。同时，氨合成尿素的速率（高度依赖ATP供应的过程）几乎完全从104 ± 10 μmol g1/h降至13 ± 6 μ mol g1/h。另一个能量依赖性过程，胆汁流量也通过Wy-14.643在体内处理24小时而显著减少。总之，这些数据表明，由于Wy-14.643解偶联氧化磷酸化，体内细胞过程（如尿素合成和胆汁流）的能量供应被破坏。有人提出，过氧化物酶体增殖物积累在肝脏中，它们解偶联线粒体氧化磷酸化和干扰细胞能量。
A number of plasticizers and lipid-lowering drugs induce peroxisomes and cause hepatocellular carcinoma in rodents by mechanisms which remain unknown. In this study, seven structurally dissimilar peroxisome proliferating agents were shown to uncouple oxidative phosphorylation in isolated rat liver mitochondria. For example, perfluorooctanoate (0.5 mM) increased succinate-induced (state 4) mitochondrial respiration by over 50% while stimulation of state 3 respiration with ADP was minimal (i.e., uncoupling occurred). Interestingly, compounds which are potent carcinogens in vivo (e.g. Wy-14.643 and perfluorooctanoate) were more powerful uncouplers of oxidative phosphorylation in vitro than weak tumor-causing agents (e.g., valproate). Uncoupling also occurred in vivo. Basal rates of oxygen uptake in perfused livers from chronically treated rats were increased from 137 ± 7 μmol g1/h in pair-fed controls to 153 ± 5 μmol g1/h after 2.5 months of feeding Wy-14.643 (0.1% w/v in diet). Concomitantly, rates of urea synthesis from ammonia, a process highly dependent on ATP supply, were reduced almost completely from 104 ± 10 μmol g1/h to 13 ± 6 μol g1/h. Bile flow, another energy dependent process, was also reduced significantly by treatment with Wy-14.643 in vivo for 24 h. Taken together, these data indicate that energy supply for cellular processes such as urea synthesis and bile flow was disrupted in vivo due to uncoupling of oxidative phosphorylation by Wy-14.643. It is proposed that peroxisomal proliferators accumulate in the liver where they uncouple mitochondrial oxidative phosphorylation and interfere with cellular energetics.