Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome.
Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome.
复制标题
线粒体通透性转变在水杨酸盐对培养大鼠肝细胞毒性中的作用：对雷氏综合征发病机制的影响。
DOI：
10.1006/taap.1997.8313
复制
发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Lemasters,JJ
中科院分区：
文献类型：
--
作者：
Trost,LC;Lemasters,JJ
阿司匹林与雷氏综合征的发病机制密切相关，雷氏综合征是一种以高氨血症、微囊性脂肪变性和脑病为特征的儿童疾病。先前，我们发现阿司匹林的活性代谢物水杨酸盐在分离的线粒体中诱导线粒体通透性转变（MPT），其他几种与雷氏相关疾病有关的化学物质也是如此。在线粒体内膜上打开一个高电导的环孢素a敏感孔，引起MPT，导致氧化磷酸化的肿胀、去极化和解偶联。本研究的目的是表征MPT在水杨酸对培养大鼠肝细胞毒性中的作用。水杨酸（0.3 ~ 5mm）引起浓度依赖性细胞杀伤。在Krebs-Ringer缓冲液中，3 mM水杨酸后150分钟出现半最大细胞杀伤。增加Ca2+可增强水杨酸盐的致死率。0.5-5 μM环孢素A及其非免疫抑制类似物4-甲基缬氨酸环孢素可阻断水杨酸盐依赖性细胞杀伤，提示MPT参与细胞杀伤的发病机制。激光扫描共聚焦显微镜证实了MPT对致死性细胞损伤的贡献，结果表明，在细胞杀伤之前，荧光团钙黄蛋白从细胞质重新分配到线粒体中，这一事件被环孢素a阻断，水杨酸盐毒性在高细胞外Ca2+时增强。在10-100 μM范围内，几种化学上不同的钙拮抗剂阻断或降低了水杨酸盐的毒性，包括维拉帕米、地尔硫卓、氯丙嗪、硝苯地平和尼索地平。钙拮抗剂也阻断了高Ca2+缓冲液中线粒体游离Ca2+的增加，这是通过荧光团Rhod-2的共聚焦成像确定的。这些与水杨酸相关的数据表明，MPT的发作可能是导致Reye综合征线粒体损伤和Reye相关药物毒性的常见病理生理机制。此外，线粒体内Ca2+升高可能是Reye's相关化学物质促进MPT发病的易感条件。
Aspirin is strongly implicated in the pathogenesis of Reye's syndrome, a childhood disorder characterized by hyperammonemia, microvesicular steatosis, and encephalopathy. Previously, we showed that salicylate, the active metabolite of aspirin, induces the mitochondrial permeability transition (MPT) in isolated mitochondria, as do several other chemicals implicated in Reye's-related disorders. Opening of a high conductance, cyclosporin A–sensitive pore in the mitochondrial inner membrane causes the MPT, leading to swelling, depolarization, and uncoupling of oxidative phosphorylation. The goal of this study was to characterize the role of the MPT in salicylate toxicity to cultured rat hepatocytes. Salicylate (0.3–5 mM) caused concentration-dependent cell killing. In Krebs–Ringer buffer, half-maximal cell killing occurred 150 min after 3 mM salicylate. Increasing Ca2+enhanced salicylate lethality. Salicylate-dependent cell killing was blocked by 0.5–5 μM cyclosporin A and its nonimmunosuppresive analog, 4-methylvaline cyclosporin, implicating the MPT in the pathogenesis of cell killing. The contribution of the MPT to lethal cell injury was confirmed by laser scanning confocal microscopy, which demonstrated the redistribution of the fluorophore calcein from the cytosol into mitochondria prior to cell killing, an event blocked by cyclosporin A. Salicylate toxicity was enhanced at high extracellular Ca2+. In the range of 10–100 μM, several chemically diverse calcium antagonists blocked or reduced salicylate toxicity including verapamil, diltiazem, chlorpromazine, nifedipine, and nisoldipine. Calcium antagonists also blocked the increase of mitochondrial free Ca2+in high Ca2+buffer, as determined by confocal imaging of the fluorophore Rhod-2. These data with salicylate suggest that onset of the MPT may be the common pathophysiologic mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities. Further, elevated intramitochondrial Ca2+may be a predisposing condition promoting onset of the MPT by Reye's-related chemicals.
登录
查看更多内容
影响因子：
4.5
作者：
Paola Costantini;V. Petronilli;R. Colonna;Paolo Bernardi
通讯作者：
Paolo Bernardi
亲免素药物复合物抑制 T 细胞信号通路：副作用是免疫抑制特性固有的吗？
影响因子：
0.9
作者：
M. Schreier;G. Baumann;G. Zenke
通讯作者：
G. Zenke
DOI：
--
发表时间：
1988
期刊：
影响因子：
--
作者：
P. Pinsky;E. Hurwitz;L. Schonberger;W. Gunn
通讯作者：
W. Gunn
急性甲萘醌给药后线粒体通透性转变的诱导增强。
影响因子：
3.9
作者：
K. Saxena;T. Henry;L. Solem;K. Wallace
通讯作者：
K. Wallace
阿司匹林诱导表达线粒体靶向绿色荧光蛋白（mtGFP）的大鼠肝细胞线粒体改变
影响因子：
3.5
作者：
R. Venerando;G. Miotto;P. Pizzo;R. Rizzuto;N. Siliprandi
通讯作者：
N. Siliprandi