Tsai Ming-Shiun, Chien Chia-Chih, Lin Ting-Hui, Liu Chia-Chi, Liu Rosa Huang, Su Hong-Lin, Chiu Yung-Tsung, Wang Sue-Hong
1 Department of Bioindustry Technology, Da-Yeh University , Taiwan, Republic of China .
2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China .
J Med Food. 2015 Nov;18(11):1187-97. doi: 10.1089/jmf.2014.3328. Epub 2015 Jun 4.
Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model.
对乙酰氨基酚（APAP）过量会导致严重的肝损伤和肾损伤。APAP诱导的肝损伤（AILI）是药物性肝衰竭最常见的原因。APAP相对不溶，只能口服；然而，其前体药物丙帕他莫是水溶性的，通常直接注射。在本研究中，我们检测了丙帕他莫注射后小鼠AILI的时间依赖性效应。通过分析丙氨酸转氨酶和天冬氨酸转氨酶活性以及肝脏组织病理学，我们证明单次注射丙帕他莫可建立一种新型的AILI小鼠模型。此外，我们在模型小鼠中比较了高良姜素与已知的肝脏保护提取物水飞蓟宾以及唯一用于治疗APAP毒性的临床药物N - 乙酰半胱氨酸（NAC）在相同剂量下的保护和治疗效果。我们观察到，在预防AILI方面，高良姜素和水飞蓟宾比NAC更有效。然而，只有NAC能显著提高致死剂量丙帕他莫后的存活时间和存活率。为了解析高良姜素的肝脏保护机制，高良姜素预处理显著降低了肝脏氧化应激，提高了肝脏谷胱甘肽水平，并降低了丙帕他莫注射诱导的肝脏微粒体CYP2E1水平。此外，丙帕他莫注射还重现了APAP诱导的肾损伤（AIKI）的可能性，类似于临床APAP过量。只有高良姜素预处理显示出对AIKI的保护作用。因此，我们通过单次注射丙帕他莫建立了一种新型的AILI和AIKI小鼠模型。我们还证明，在该小鼠模型中，高良姜素对AILI和AIKI具有显著的保护作用。
