組胺酸、半胱胺酸及其衍生物對抗不同肝臟傷害之動物研究

慢性肝病及肝硬化在台灣的患者很多，因此預防及治療刻不容緩。造成慢性肝病及肝硬化的原因非常多樣性，本研究係針對因酒精性脂肪肝所導致的慢性肝炎和因非酒精性脂肪肝所導致的肝纖維化及肝硬化兩個部分進行探討。利用動物模式探討組胺酸、半胱胺酸及其衍生物預防及/或改善肝臟傷害的效果及機轉。 第一部份是探討組胺酸和肌肽對酒精誘發之慢性肝損傷所造成的影響。用70%酒精經口誘發老鼠慢性肝損傷4週後，分別以每公升飲用水添加0.5、1和2克的組胺酸或肌肽處理3週後進行實驗。結果顯示組胺酸或肌肽的攝取可顯著地降低丙胺酸轉胺酶和天門冬胺酸轉胺酶的活性，並可減少丙二醛的產生，增加麩胱苷肽的含量，增強過氧化氫酶和麩胱苷肽過氧化酶的活性，且抑制細胞色素P450 2E1酵素活性，減少C反應蛋白、介白素-6和腫瘤壞死因子-alpha的釋放。隨著組胺酸或肌肽的攝取濃度增加，會向上調控增加過氧化氫酶mRNA的表現，並向下調控介白素-6和腫瘤壞死因子-alpha的mRNA表現。 第二章的研究是探討半胱胺酸衍生物對甲硫胺酸與膽鹼缺乏飲食誘發之肝臟脂質代謝異常的影響。以甲硫胺酸與膽鹼缺乏的飲食餵食並分別以每公升飲水中添加1克的半胱胺酸衍生物(SAC或SEC)處理7週後進行實驗。結果顯示半胱胺酸衍生物的攝取可有效地減少肝臟三酸甘油酯的堆積，並可降低6-磷酸葡萄糖去氫酶和脂肪酸合成酶的活性，增加血液及肝臟中麩胱苷肽的濃度，減少丙二醛和氧化型麩胱苷肽的產生，且恢復麩胱苷肽過氧化酶、超氧化物歧化酶和過氧化氫酶的活性及mRNA的表現。另外，甲硫胺酸與膽鹼缺乏飲食也會造成介白素-1beta、介白素-6、腫瘤壞死因子-alpha、移轉型生長因子-beta1、基質金屬蛋白酶-9和膠原-alpha1的mRNA表現增加，而半胱胺酸衍生物的攝取可有效的減弱介白素-1beta、介白素-6、腫瘤壞死因子-alpha、移轉型生長因子-beta1和膠原-alpha1的mRNA表現。 基於以上研究結果得知，組胺酸、半胱胺酸及其衍生物對於緩和肝損傷是有幫助。

Chronic hepatopathy and liver cirrhosis are common liver disease in Taiwan. There are extraordinary variety of causes responsible for chronic hepatopathy and liver cirrhosis. In this study, by using animal model, we investigated the protective effect of histidine, cysteine and its derivatives on ethanol-induced chronic hepatitis and nonalcoholic steatohepatitis-induced liver fibrosis and cirrhosis. First, the effects of histidine and carnosine on ethanol-induced chronic liver injury was examined. Mice were treated four weeks by 70% ethanol (p.o.) to induce chronic liver injury and followed by histidine or carnosine treatment for three weeks, in which histidine or carnosine, each agent at 0.5, 1 and 2 gram per liter, was added to the drinking water. These results showed that the post-intake of histidine or carnosine markedly decreased these activities of alanine aminotransferase and aspartate aminotransferase and diminished the formation MDA, elevated GSH content, enhanced catalase and GPX activities, suppressed CYP2E1 activity, and diminished the release of CRP, IL-6 and TNF-alpha. Histidine and carnosine post-treatments significantly up-regulated the expression of catalase mRNA, and down-regulated mRNA expression of IL-6 and TNF-alpha. Second, the alleviative effects of cysteine derivatives (SAC and SEC) on MCD diet-induced hepatotoxicity was examined. SAC or SEC at 1 gram per liter was added into drinking water for seven weeks with MCD diet. Results showed that the intake of SAC or SEC significantly decreased hepatic triglyceride accumulation, reduced G6PDH and FAS activities, increased serum and hepatic GSH levels, decreased MDA and GSSG formation, and restored the activity and mRNA expression of GPX, SOD and catalase. MCD feeding significantly enhanced the mRNA expression of IL-1beta, IL-6, TNF-alpha, TGF-beta1, MMP-9 and collagen-alpha1. The intake of SAC and SEC significantly blunted the mRNA expression of IL-1beta, IL-6, TNF-alpha, TGF-beta1 and collagen-alpha1. These results support that the supplement of histidine, cysteine and its derivatives might be helpful for attenuating different hepatotoxicity.