Establishment of a standardized animal model of chronic hepatotoxicity using acetaminophen-induced hepatotoxicity in the evaluation of hepatoprotective effects of health food
Other Title
建立乙醯氨酚慢性肝損傷動物模式
Journal
Journal of Food and Drug Analysis
Journal Volume
20
Journal Issue
1
Start Page
41
End Page
47+167
Date Issued
2012
Author(s)
Chen, Pei-Ju
Chen, Ting-Ju
Hu, Fang-Ching
Chi, Wei-Ting
Chou, Hsiao-Yin
Chiu, Hsien-Chiao
Lee, Yu-Chun
Abstract
Hepatoprotection is an important issue in Taiwan. Currently, a toxic chemical substance, carbon tetrachloride (CCl4), is used to induce liver damage in animal models that is employed to evaluate the hepatoprotective effects of health food in Taiwan. To provide a more flexible and accessible research model, this study was aimed to establish a standardized animal model of chronic hepatotoxicity using the common drug, acetaminophen; an overdose of this drug causes acute liver damage in experimental animals. Four animal strains from 2 species (ICR mice and BALB/c mice via intraperitoneal injection; Sprague-Dawley rats and Wistar rats via oral administration) were used as subjects in this study. Acetaminophen at various dosages was administered for 8 weeks, and then biochemical and histopathological examinations were performed. The results showed that acetaminophen significantly induced liver damage in mice by intraperitoneal injection, but not in rats by oral administration. The individual variation in BALB/c mice was less than that in ICR mice. Acetaminophen increased serum aspartate transaminase (AST), alanine transaminase (ALT), and glutathione (GSH) content. The glutathione reductase (GRd), superoxide dismutase (SOD), and catalase (CAT) activity were inhibited after acetaminophen injection in BALB/c mice in a dose-dependent manner. The highest dose of acetaminophen was lethal to mice. In terms of histopathological examination, acetaminophen caused hepatic necrosis and inflammation, consistent with the pathological progress found in humans. On the other hand, the liver protective effect of N-acetylcysteine (NAC) in BALB/c mice was analyzed. The data revealed that pretreatment with NAC significantly protected liver from damage induced by 400 mg acetaminophen/kg bw in BALB/c mice, and there was no significant difference between the 600 and 1200 mg NAC/kg bw groups. In conclusion, acetaminophen at the dose of 400 mg/kg bw could induce reproducible liver damage in BALB/c mice, and NAC (600 mg/kg bw) is a suitable protective drug in this animal model for the evaluation of hepatoprotective effects of health food.
護肝相關議題深受台灣人所關注，目前台灣使用的護肝功效健康食品評估辦法，是以四氯化碳誘導肝損傷為動物模式，但由於四氯化碳是少見的藥物，且已被列為毒性化學物質，故本研究目的為建立標準化的乙醯氨酚誘導動物慢性肝損傷模式，以提供一更適宜的研究模式。本實驗採用的實驗動物為大鼠與小鼠兩個品系，使用最常見的ICR與BALB/c小鼠，以及Sprague-Dawley與Wistar大鼠，在接受不同劑量的乙醯氨酚八周後，進行生化檢測與組織切片。實驗結果顯示，乙醯氨酚能顯著的誘導小鼠肝損傷，但對大鼠則無顯著性傷害。在小鼠中，BALB/c小鼠的個體差異又較ICR小鼠小。乙醯氨酚的投予能顯著增高BALB/c小鼠血清中麩草醋醯轉胺酶、麩丙酮醯轉胺酶、與殼胱甘肽之含量，並顯著的降低殼胱甘肽還原酶、超氧化歧化酶、與過氧化氫酶等酵素活性，且具有劑量效應。在肝臟組織切片中，可以看到乙醯氨酚造成肝臟發炎與壞死，其病理進展與人體相似。由於實驗中使用的最高劑量（600 mg/kg bw）乙醯氨酚對小鼠具有致命的毒性，因此建議以中劑量（400 mg/kg bw）乙醯氨酚作為誘導BALB/c小鼠肝中損傷之劑量。本研究進一步探討N－乙醯基半胱氨酸在BALB/c小鼠中的護肝效果，結果顯示預先使用600與1200 mg/kg bw N－乙醯基半胱氨酸能顯著預防400 mg/kg bw乙醯氨造成的肝損傷，二劑量間並無顯著差異。本研究結果建立了乙醯氨酚誘導動物肝損傷模式，實驗結果證實使用40() mg/kg乙醯氨酚能成功誘導BALB/c小鼠肝損傷，且具有再現性，而600 mg/kg bw N－乙醯基半胱氨酸能作為此動物模式下的護肝藥物。
Subjects
Acetaminophen
ICR mice
BALB/c mice
SD rats
Wistar rats
health foods
liver damage
NAC
乙醯氨酚
ICR小鼠
BALB/c小鼠
SD大鼠
Wistar大鼠
健康食品
肝損傷
N－乙醯基半胱氨酸
Type
journal article