Role of cellular energy status in tocopheryl hemisuccinate cytoprotection against ethyl methanesulfonate-induced toxicity.
Role of cellular energy status in tocopheryl hemisuccinate cytoprotection against ethyl methanesulfonate-induced toxicity.
复制标题
细胞能量状态在生育酚半琥珀酸酯针对甲磺酸乙酯诱导的毒性的细胞保护中的作用。
DOI：
10.1006/abbi.1994.1224
复制
发表时间：
1994
影响因子：
3.9
通讯作者：
Fariss,MW
中科院分区：
文献类型：
--
作者：
Ray,SD;Fariss,MW
我们实验室的既往研究表明，给予α-生育酚半琥珀酸酯（TS）（而非未酯化的α-生育酚（T））可保护肝细胞免受各种毒性损伤，包括化学品、药物、金属和氧化应激。这种独特的细胞保护作用的一种可能机制是，从细胞TS释放的琥珀酸盐在毒性攻击期间用作补充能量来源。为了验证这一假设，我们检查了TS（25 μM）给药对细胞活力、脂质过氧化和几种细胞能量相关过程的影响，如在使用烷化剂甲磺酸乙酯（EMS）进行毒性挑战期间，离体肝细胞悬液中的线粒体膜电位（MMP，Δ）、乳酸盐形成以及ATP和K+浓度。来自这些研究的数据表明，EMS处理导致孵育2小时后的快速细胞死亡和脂质过氧化。在EMS诱导的细胞死亡之前，MMP、细胞内ATP和K+水平、线粒体超微结构以及细胞乳酸产生的短暂增加迅速丧失。EMS暴露前用TS预处理肝细胞可防止MMP损失和线粒体超微结构变化以及脂质过氧化和细胞死亡。细胞ATP水平和乳酸生产没有反映提供给TS处理的肝细胞的保护。当肝细胞：（i）用TS和酯酶抑制剂预处理（防止TS释放T和琥珀酸酯）;（ii）用其他亲脂性琥珀酸酯衍生物（胆固醇半琥珀酸酯、琥珀酸单甲酯和琥珀酸二甲酯）预处理;或（iii）用T和琥珀酸钠预处理时，未观察到对EMS诱导毒性的保护。与琥珀酸单甲酯不同，细胞保护性TS预处理不刺激糖原合成或糖酵解。与TS预处理大鼠不同，T预处理24 h的大鼠分离的肝细胞不受EMS毒性作用的保护。总之，TS对线粒体毒物EMS的细胞保护似乎与TS在肝细胞中的积累和线粒体功能（MMP）的维持有关。根据我们早期的研究结果和目前的观察，我们建议，一个独特的亚细胞处置TS和随后的释放T和琥珀酸在一个关键的线粒体网站是负责观察到的细胞保护。
Previous studies from our laboratory have demonstrated that the administration of α-tocopheryl hemisuccinate (TS),but not unesterified α-tocopherol (T), protects hepatocytes from a variety of toxic insults including chemicals, drugs, metals, and oxidative stress. One possible mechanism for this unique cytoprotection is that succinate released from cellular TS is used as a supplemental energy source during a toxic challenge. To test this hypothesis, we examined the effect of TS (25 μM) administration on cell viability, lipid peroxidation, and several cellular energy-related processes such as mitochondrial membrane potential (MMP, ΨΔ), lactate formation, and ATP and K+concentrations in isolated hepatocyte suspensions during a toxic challenge with the alkylating agent, ethyl methanesulfonate (EMS). Data from these studies demonstrate that EMS treatment results in rapid cell death and lipid peroxidation following 2 h of incubation. Preceding EMS-induced cell death was a rapid loss of MMP, intracellular ATP and K+levels, and mitochondrial ultrastructure as well as a transient increase in cellular lactate production. Pretreatment of hepatocytes with TS prior to EMS exposure prevented the loss of MMP and mitochondrial ultrastructural changes as well as lipid peroxidation and cell death. Cellular ATP levels and lactate production did not reflect the protection afforded to TS-treated hepatocytes. Protection against EMS-induced toxicity was not observed when hepatocytes were: (i) pretreated with TS and esterase inhibitors (preventing T and succinate release from TS); (ii) pretreated with other lipophilic succinate derivatives (cholesteryl hemisuccinate, monomethyl and dimethyl succinate); or (iii) pretreated with T and sodium succinate. Unlike monomethyl succinate, cytoprotective TS pretreatment did not stimulate gluconeogenesis or glycolysis. Hepatocytes isolated from rats pretreated for 24 h with T were not protected from the toxic effects of EMS, unlike TS-pretreated rats. In conclusion, TS cytoprotection against the mitochondrial toxicant EMS appears to be related to the hepatocellular accumulation of TS and the maintenance of mitochondrial function (MMP). Based on our earlier findings and the present observations, we propose that a unique subcellular disposition for TS and the subsequent release of T and succinate at a critical mitochondrial site is responsible for the observed cytoprotection.