ACETAMINOPHEN-INDUCED INHIBITION OF HEPATIC MITOCHONDRIAL RESPIRATION IN MICE
ACETAMINOPHEN-INDUCED INHIBITION OF HEPATIC MITOCHONDRIAL RESPIRATION IN MICE
复制标题
DOI：
10.1016/0041-008x(88)90040-3
复制
发表时间：
1988-05-01
影响因子：
3.8
通讯作者：
COHEN, SD
中科院分区：
文献类型：
--
作者：
MEYERS, LL;BEIERSCHMITT, WP;COHEN, SD
在对乙酰氨基酚（APAP）肝毒性过程的早期，在线粒体中观察到形态学变化。为了确定是否也发生功能缺陷，本研究检查了APAP在体内和体外对禁食雄性CD-1小鼠（3-4月龄）线粒体呼吸的影响。在肝毒性剂量的APAP（600 mg/kg，po）后，当谷氨酸被用作呼吸底物时，状态3呼吸（ADP刺激）被抑制，这反映在呼吸控制率（RCR）降低。相反，当琥珀酸是呼吸底物时，RCR的降低反映了状态4（静息）呼吸的增加。无肝毒性剂量的APAP（300 mg/kg，po）后没有检测到影响。这些APAP诱导的呼吸作用和肝毒性可通过胡椒基丁醚预处理来预防，并且在1个月和2个月大的小鼠中不存在，这些小鼠对APAP诱导的损伤具有抗性。由于APAP诱导的体内线粒体呼吸抑制与年龄相关和胡椒基丁醚依赖性毒性差异相关，因此数据表明体内效应至少部分来自混合功能氧化酶产生的代谢物。在体外，无论是状态3和状态4呼吸，以及RCR，抑制APAP以浓度依赖性的方式与谷氨酸作为底物。然而，没有观察到效果与琥珀酸作为底物，从而与体内暴露后获得的结果形成对比。因此，APAP的体外作用与体内观察到的作用不同，可能是母体化合物的直接损伤所致。这些研究表明，线粒体功能的早期改变可能是APAP肝毒性的重要机制。
Morphological changes are observed in mitochondria early in the course of acetaminophen (APAP) hepatotoxicity. In order to determine if functional deficits also occurs, this study examined the effect of APAP, in vivo and in vitro, on mitochondrial respiration in fasted, male CD-1 mice (3-4 months old). After a hepatotoxic dose of APAP (600 mg/kg, po), when glutamate was used as the respiratory substrate, state 3 respiration (ADP-stimulated) was inhibited and this was reflected in a decreased respiratory control ratio (RCR). In contrast, when succinate was the respiratory substrate, the decreased RCR was reflective of an increase in state 4 (resting) respiration. There was no detectable effect after an nonhepatotoxic dose of APAP (300 mg/kg, po). These APAP-induced respiratory effects and hepatotoxicity were prevented by piperonyl butoxide pretreatment, and were absent in 1- and 2-month-old mice, which are resistant to APAP-induced damage. Since the APAP-induced inhibition of mitochondrial respiration, in vivo, correlated with age-related and piperonyl butoxide-dependent differences in toxicity, the data suggest that the in vivo effects result, at least in part, from a mixed-function oxidase generated metabolite. In vitro, both state 3 and state 4 respiration, as well as the RCR, were inhibited by APAP in a concentration-dependent manner with glutamate as substrate. However, no effects were observed with succinate as substrate, thereby contrasting with results obtained following in vivo exposure. Therefore the in vitro effects of APAP are different from those observed in vivo and may result from a direct insult of the parent compound. These studies suggest that early alterations in mitochondrial function may be mechanistically important in APAP hepatoxicity.