Meyers L L, Beierschmitt W P, Khairallah E A, Cohen S D
Department of Pharmacology and Toxicology, University of Connecticut, Storrs 06268.
Toxicol Appl Pharmacol. 1988 May;93(3):378-87. doi: 10.1016/0041-008x(88)90040-3.
Morphological changes are observed in mitochondria early in the course of acetaminophen (APAP) hepatotoxicity. In order to determine if functional deficits also occur, 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 a 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 hepatotoxicity.
在对乙酰氨基酚（APAP）肝毒性病程早期，线粒体中可观察到形态学变化。为确定是否也会出现功能缺陷，本研究在体内和体外检测了APAP对禁食的3 - 4月龄雄性CD - 1小鼠线粒体呼吸的影响。给予肝毒性剂量的APAP（600 mg/kg，口服）后，当以谷氨酸作为呼吸底物时，状态3呼吸（ADP刺激的）受到抑制，这反映在呼吸控制率（RCR）降低。相反，当琥珀酸作为呼吸底物时，RCR降低反映了状态4（静息）呼吸增加。给予非肝毒性剂量的APAP（300 mg/kg，口服）后未检测到影响。胡椒基丁醚预处理可预防这些APAP诱导的呼吸效应和肝毒性，且在对APAP诱导损伤具有抗性的1月龄和2月龄小鼠中不存在这些效应。由于体内APAP诱导的线粒体呼吸抑制与年龄相关及胡椒基丁醚依赖性的毒性差异相关，数据表明体内效应至少部分源于混合功能氧化酶产生的代谢产物。在体外，以谷氨酸作为底物时，APAP以浓度依赖性方式抑制状态3和状态4呼吸以及RCR。然而，以琥珀酸作为底物时未观察到影响，这与体内暴露后的结果形成对比。因此，APAP的体外效应与体内观察到的不同，可能源于母体化合物的直接损伤。这些研究表明，线粒体功能的早期改变在APAP肝毒性中可能具有重要的机制意义。
