Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710038, China.
Exp Biol Med (Maywood). 2021 May;246(10):1219-1227. doi: 10.1177/1535370220977823. Epub 2020 Dec 20.
Overdose of acetaminophen (APAP) is responsible for the most cases of acute liver failure worldwide. Hepatic mitochondrial damage mediated by neuronal nitric oxide synthase- (nNOS) induced liver protein tyrosine nitration plays a critical role in the pathophysiology of APAP hepatotoxicity. It has been reported that pre-treatment or co-treatment with glycyrrhizin can protect against hepatotoxicity through prevention of hepatocellular apoptosis. However, the majority of APAP-induced acute liver failure cases are people intentionally taking the drug to commit suicide. Any preventive treatment is of little value in practice. In addition, the hepatocellular damage induced by APAP is considered to be oncotic necrosis rather than apoptosis. In the present study, our aim is to investigate if glycyrrhizin can be used therapeutically and the underlying mechanisms of APAP hepatotoxicity protection. Hepatic damage was induced by 300 mg/kg APAP in balb/c mice, followed with administration of 40, 80, or 160 mg/kg glycyrrhizin 90 min later. Mice were euthanized and harvested at 6 h post-APAP. Compared with model controls, glycyrrhizin post-treatment attenuated hepatic mitochondrial and hepatocellular damages, as indicated by decreased serum glutamate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase activities as well as ameliorated mitochondrial swollen, distortion, and hepatocellular necrosis. Notably, 80 mg/kg glycyrrhizin inhibited hepatic nNOS activity and its mRNA and protein expression levels by 16.9, 14.9, and 28.3%, respectively. These results were consistent with the decreased liver nitric oxide content and liver protein tyrosine nitration indicated by 3-nitrotyrosine staining. Moreover, glycyrrhizin did not affect the APAP metabolic activation, and the survival rate of ALF mice was increased by glycyrrhizin. The present study indicates that post-treatment with glycyrrhizin can dose-dependently attenuate hepatic mitochondrial damage and inhibit the up-regulation of hepatic nNOS induced by APAP. Glycyrrhizin shows promise as drug for the treatment of APAP hepatotoxicity.
对乙酰氨基酚（APAP）过量是导致全球大多数急性肝衰竭的原因。神经元型一氧化氮合酶（nNOS）诱导的肝蛋白酪氨酸硝化介导的肝线粒体损伤在 APAP 肝毒性的病理生理学中起着关键作用。据报道，甘草酸苷的预处理或共同处理可以通过防止肝细胞凋亡来保护肝脏免受毒性作用。然而，大多数 APAP 诱导的急性肝衰竭病例是人们故意服用药物自杀。在实践中，任何预防治疗都没有什么价值。此外，APAP 诱导的肝细胞损伤被认为是膨胀性坏死而不是细胞凋亡。在本研究中，我们的目的是研究甘草酸苷是否可以用于治疗，并探讨 APAP 肝毒性保护的潜在机制。在 Balb/c 小鼠中用 300mg/kg APAP 诱导肝损伤，90 分钟后给予 40、80 或 160mg/kg 甘草酸苷。在 APAP 后 6 小时处死小鼠并采集样本。与模型对照组相比，甘草酸苷治疗后减轻了肝线粒体和肝细胞损伤，血清谷氨酸脱氢酶、丙氨酸转氨酶和天冬氨酸转氨酶活性降低，线粒体肿胀、变形和肝细胞坏死得到改善。值得注意的是，80mg/kg 甘草酸苷分别抑制了肝 nNOS 活性及其 mRNA 和蛋白表达水平的 16.9%、14.9%和 28.3%。这些结果与 3-硝基酪氨酸染色所示的肝一氧化氮含量和肝蛋白酪氨酸硝化减少一致。此外，甘草酸苷不影响 APAP 的代谢激活，且甘草酸苷增加了 ALF 小鼠的存活率。本研究表明，甘草酸苷后处理可剂量依赖性减轻肝线粒体损伤，并抑制 APAP 诱导的肝 nNOS 上调。甘草酸苷有望成为治疗 APAP 肝毒性的药物。
