Oxidative stress contributes to acetaminophen (APAP) hepatotoxicity. Since lipid peroxidation produces reactive aldehydes, we investigated whether activation of mitochondrial aldehyde dehydrogenase-2 (ALDH2) with Alda-1 decreases liver injury after APAP. Male C57BL/6 mice fasted overnight received Alda-1 (20 mg/kg, i.p.) or vehicle 30 min before APAP (300 mg/kg, i.p.). Blood and livers were collected 2 or 24 h after APAP. Intravital multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide (PI) fluorescence was conducted 6 h after APAP administration to detect mitochondrial polarization status and cell death. 4-Hydroxynonenal protein adducts were present in 0.1% of tissue area without APAP treatment but increased to 7% 2 h after APAP treatment, which Alda-1 blunted to 1%. Serum alanine and aspartate aminotransferases increased to 7594 and 9768 U/L at 24 h respectively, which decreased ≥72% by Alda-1. Alda-1 also decreased centrilobular necrosis at 24 h after APAP from 47% of lobular areas to 21%. N-acetyl-p-benzoquinone imine protein adduct formation and c-Jun-N-terminal kinase phosphorylation increased after APAP as expected, but Alda-1 did not alter these changes. Without APAP, no mitochondrial depolarization was detected by intravital microscopy. At 6 h after APAP, 62% of tissue area showed depolarization, which decreased to 33.5% with Alda-1. Cell death as detected by PI labeling increased from 0 to 6.8 cells per 30× field 6 h after APAP, which decreased to 0.6 cells by Alda-1. In conclusion, aldehydes are important mediators of APAP hepatotoxicity. Accelerated aldehyde degradation by ALDH2 activation with Alda-1 decreases APAP hepatotoxicity by protection against mitochondrial dysfunction.

中文翻译：

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醛脱氢酶2激活可通过防止线粒体去极化来降低对乙酰氨基酚的肝毒性。

氧化应激会导致对乙酰氨基酚（APAP）肝毒性。由于脂质过氧化会产生活性醛，因此我们研究了用Alda-1激活线粒体醛脱氢酶2（ALDH2）是否能减少APAP后的肝损伤。禁食过夜的雄性C57BL / 6小鼠在APAP前30分钟接受Alda-1（20 mg / kg，ip）或溶媒（300 mg / kg，ip）。APAP后2或24小时收集血液和肝脏。APAP给药后6小时进行了若丹明123（Rh123）和碘化丙啶（PI）荧光的活体多光子显微镜检查，以检测线粒体的极化状态和细胞死亡。未经APAP处理的组织中0.1％存在4-羟基壬醛蛋白加合物，但在APAP处理后2 h增加到7％，Alda-1减弱至1％。血清丙氨酸和天冬氨酸转氨酶在24 h分别升高至7594和9768 U / L，而Alda-1降低≥72％。Alda-1还可以在APAP后24小时将小叶坏死从47％的小叶区域减少到21％。APAP后，N-乙酰基-对-苯醌亚胺亚胺蛋白加合物的形成和c-Jun-N-端激酶的磷酸化增加，但Alda-1并未改变这些变化。没有APAP，通过活体内显微镜检查未检测到线粒体去极化。APAP后6小时，有62％的组织区域显示去极化，而Alda-1减少到33.5％。通过PI标记检测到的细胞死亡在APAP后6小时每30x场从0增加到6.8细胞，而通过Alda-1减少到0.6细胞。总之，醛是APAP肝毒性的重要介质。