肝臟為人體中主要執行解毒及代謝作用的重要器官，當肝功能損傷時會造成代謝障礙並影響到其他臟器的功能，嚴重則危及生命。乙醯胺基苯酚 (acetaminophen, APAP) 為國人常用解熱鎮痛藥物的主要成分，而近年來許多研究發現食用過量 APAP 易造成嚴重的肝腎損傷。本研究乃針對可能具護肝潛力之中藥食材陳皮 (Chenpi, CP) 進行肝臟保健功效評估與其機轉作用探討。首先以 HepG2-C8 細胞評估陳皮熱水粗萃物 (water extract, WE)、乙醇粗萃物 (ethanolic extract, EE) 及熱水萃取後殘渣乙醇粗萃物 (water extraction residue ethanolic extract, WREE) 誘導 ARE-luciferase 活性之能力，其中 CP-WREE (100 μg/mL) 最能有效提升 Nrf2路徑活性。HPLC 結果證實 CP-WREE 富含橘皮素 (tangeretin) 和川陳皮素 (nobiletin)，分別為13.4和45 mg/100 g dry extract。CP-WREE 亦對 APAP 誘導小鼠 AML-12 正常肝細胞損傷具有顯著性的保護作用，能降低 APAP 誘導脂質過氧化情形。進一步發現 CP-WREE顯著增加 AML-12 細胞內 Nrf2 與 Nrf2 下游抗氧化/解毒酵素 (HO-1、NQO1 及 UGT1A) mRNA 和蛋白質表現，亦改變表觀遺傳學修飾酵素 (包括 Dnmts、HDACs 及 KDMs) 之蛋白質表現。上述結果顯示，CP-WREE 對 APAP 誘導 AML-12 細胞損傷的保護作用可能透過表觀遺傳調控 Nrf2 /抗氧化路徑，故本研究結果可供日後保健食品開發和生物醫學研究之重要參考。

The liver is a critical organ responsible for the detoxification and metabolism in the human body. Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but it has been demonstrated that excessive consumption of APAP can cause severe liver and kidney damage. Aged citrus peel (Chenpi, CP) is a Chinese herb with hepatoprotective potential to be usually used as foods in Taiwan. Three extracts of CP were prepared in this study, including water extract (CP-WE), ethanolic extract (CP-EE), and water extraction residue ethanolic extract (CP-WREE). Among these extracts, we found CP-WREE (100 μg/mL) effectively enhanced the Nrf2 pathway in HepG2-C8 cells stably transfected with ARE-luciferase construct. HPLC results showed CP-WREE contains tangeritin and nobiletin (13.4 and 45 mg/100 g dry extract, respectively). CP-WREE (50 μg/mL) also significantly protected mouse AML-12 cells from APAP-induced injury. Furthermore, CP-WREE can increase mRNA and protein levels of Nrf2 and Nrf2 downstream enzymes (HO-1, NQO1, and UGT1A) as well as the protein expressions of some epigenetic modifying enzymes (Dnmts, HDACs, and KDMs). Therefore, these results would open new avenues of approaches for the prevention of liver diseases in human.

中文摘要 I
Abstract II
謝 誌 III
目 錄 IV
表 次 IX
附錄表 IX
圖 次 X
附錄圖 XII
壹、 前言 1
貳、 文獻回顧 2
第一節、 肝臟 (liver) 與肝臟疾病 (liver disease) 2
第二節、 肝臟的解毒及代謝系統 3
第三節、 健康食品之護肝保健功效評估方法 5
一. 針對四氯化碳誘導化學性肝損傷 5
二. 針對常用止痛藥物乙醯胺基苯酚誘導化學性肝損傷 5
三. 針對應用硫代乙醯胺誘導肝纖維化之慢性肝損傷 6
四. 針對應用酒精液態飼料誘導酒精性脂肪肝 6
五. 針對高脂飼料誘導非酒精性脂肪肝 6
第四節、 乙醯胺基苯酚與肝臟代謝機制 7
一. 乙醯胺基苯酚介紹與應用 7
二. 乙醯胺基苯酚代謝機制與肝毒性影響 7
第五節、 自由基與氧化壓力對應Nrf2之護肝作用 9
一. 自由基與活性氧分子之定義 9
二. 自由基來源與氧化壓力生成 9
三. 氧化壓力與發炎反應 10
四. 抗氧化酵素系統作用機制 10
五. Nuclear factor erythroid-2-related factor-2 抗氧化機制 11
六. 天然植物化學物質活化 Nrf2路徑 12
第六節、 表觀遺傳學 (Epigenetics) 13
一. DNA 甲基化 (DNA methylation) 14
二. 組蛋白修飾 (histone modification) 14
第七節、 具護肝潛力之中藥食材 15
一. 陳皮 (citrus peel, CP) 15
二. 決明子 (cassia seed, CS) 17
三. 荷葉 (lotus leaf, LL) 18
四. 牛蒡 (burdock root, BR) 18
參、 研究目的與實驗架構 20
第一節、 研究目的 20
第二節、 實驗設計 20
第三節、 實驗架構 21
肆、 材料與方法 22
第一節、 中藥食材與多甲氧基黃酮類化合物 22
第二節、 實驗細胞株 22
第三節、 實驗藥品與耗材 22
一. 試藥與溶劑 22
二. 細胞培養藥品 23
三. 試劑分析套組 24
四. 抗體 25
五. 即時定量聚合酶連鎖反應引子 26
六. 特異性甲基化聚合酶連鎖反應 27
七. 其他 27
第四節、 實驗用儀器 28
第五節、 實驗方法 31
一. 不同溶劑中藥食材粗萃物之製備 31
二. 中藥食材粗萃物提升細胞內抗氧化能力活性之測試 32
三. 探討中藥食材粗萃物對小鼠AML12正常肝細胞之影響 35
四. 中藥食材粗萃物對APAP誘導AML-12正常肝細胞損傷之影響 45
五. 表觀遺傳學調控機制探討 48
六. 陳皮粗萃物中多甲氧基黃酮類之含量分析 50
七. 統計分析 51
伍、 結果 52
第一節、 具護肝潛力之中藥食材萃取 52
第二節、 以誘導活化 Nrf2-ARE 路徑之篩選平台 (HepG2-C8細胞株) 評估具提升細胞內抗氧化能力之中藥食材粗萃物 52
一. 中藥食材粗萃物對 HepG2-C8細胞生長之影響 52
二. 中藥食材粗萃物活Nrf2-AREs路徑之影響 53
第三節、 中藥食材粗萃物對 APAP 誘導小鼠 AML-12正常肝細胞損傷之保護作用 54
一. 評估針對 AML-12細胞生長低毒性濃度的中藥食材粗萃物對 APAP 誘導 AML-12細胞損傷之保護效果 54
二. CP-WREE 對 AML-12細胞內 Nrf2及其下游抗氧化與解毒酵素基因與蛋白質表現之影響 55
三. CP-WREE 對 APAP 誘導 AML-12細胞內脂質過氧化及抗氧化與解毒代謝系統之影響 57
第四節、 三種萃取方式之陳皮粗萃物中橘皮素 (tangeretin) 和川陳皮素 (nobiletin) 含量之分析 58
陸、 討論 59
第一節、 中藥食材粗萃物誘導 Nrf2-ARE 途徑活性之影響 59
第二節、 CP-WREE 對 AML-12細胞內 Nrf2/抗氧化路徑之影響 59
第三節、 CP-WREE 對 APAP 誘導 AML-12肝細胞損傷之影響 60
第四節、 CP-WREE中可能多甲氧基黃酮類之分析 60
柒、 結論 61
捌、 附錄 82
玖、 參考文獻 97

表 次
表一、 不同中藥食材粗萃物之回收率 62
表二、 陳皮水萃後殘渣乙醇粗萃物 (CP-WREE) 對小鼠 AML-12肝細胞內穀胱甘肽氧化酶 (GPx)、穀胱甘肽還原酶 (GRd) 及穀胱甘肽硫轉移酶 (GST) 活性之影響 63
表三、 陳皮水萃後殘渣乙醇粗萃物 (CP-WREE) 對 APAP 誘導小鼠 AML-12肝細胞內脂質過氧化 (TBARS 生成) 與穀胱甘肽氧化酶 (GPx)、穀胱甘肽還原酶 (GRd) 及穀胱甘肽硫轉移酶 (GST) 活性之影響 64
表四、 不同陳皮粗萃物中橘皮素 (tangeritin) 、川陳皮素 (nobiletin) 及 4''-demethyltangeretin 含量 65
附錄表
附表一、 SDS-PAGE 膠體製備 82
X
圖 次 圖一、 陳皮水萃物 (CP-WE) (A) 與陳皮乙醇粗萃物 (CP-EE) 和水萃後殘渣乙醇粗萃物 (CP-WREE) (B) 對人類 HepG2-C8細胞生存率之影響。 66
圖二、 決明子水萃物 (CS-WE) (A) 與決明子乙醇粗萃物 (CS-EE) 和決明子水萃後殘渣乙醇粗萃物 (CS-WREE) (B) 對人類 HepG2-C8細胞生存率之影響。 67
圖三、 荷葉水萃物 (LL-WE) (A) 與荷葉乙醇粗萃物 (LL-EE) 和荷葉水萃後殘渣乙醇粗萃物 (LL-WREE) (B) 對人類 HepG2-C8細胞生存率之影響。 68
圖四、 牛蒡水萃物 (BR-WE) (A) 與牛蒡乙醇粗萃物 (BR-EE) 和牛蒡水萃後殘渣乙醇粗萃物 (BR-WREE) (B) 對人類 HepG2-C8細胞生存率之影響。 69
圖五、 不同濃度之中藥食材粗萃物誘導 HepG2-C8細胞內 ARE-luciferase 活性之影響。 70 圖六、 陳皮水萃後殘渣乙醇萃出物 (CP-WREE) 對小鼠 AML-12正常肝細胞生存率之影響 (A) 與 APAP 誘導小鼠 AML-12肝細胞損傷之保護作用 (B)。 71 圖七、 荷葉水萃物 (LL-WE) 對小鼠 AML-12正常肝細胞生存率之影響 (A) 與 APAP 誘導小鼠 AML-12肝細胞損傷之保護作用 (B)。 72 圖八、 荷葉乙醇粗萃物(LL-EE)對小鼠AML-12正常肝細胞生存率之影響 (A)與APAP誘導小鼠AML-12肝細胞損傷之保護作用(B)。 73 圖九、 荷葉水萃後殘渣乙醇粗萃物 (LL-WREE) 對小鼠 AML-12正常肝細胞生存率之影響 (A) 與 APAP 誘導小鼠 AML-12肝細胞損傷之保
XI
護作用 (B)。 74 圖十、 牛蒡水萃後殘渣乙醇粗萃物 (BR-WREE) 對小鼠 AML-12正常肝細胞生存率之影響 (A) 與 APAP 誘導小鼠 AML-12肝細胞損傷之保護作用 (B)。 75 圖十一、 陳皮水萃後殘渣乙醇粗萃物 (CP-WREE) 對小鼠 AML-12正常肝細胞內 Nrf2與 Nrf2下游抗氧化與解毒酵素 (HO-1、NQO1和 UGT1A1) mRNA 表現量影響。 76 圖十二、 陳皮水萃後殘渣乙醇粗萃物 (CP-WREE) 對小鼠 AML-12正常肝細胞內 Nrf2與 Nrf2下游抗氧化與解毒酵素 (HO-1、NQO1及 UGT1A1) 蛋白質表現量之影響。 77 圖十三、 陳皮水萃後殘渣乙醇粗萃物(CP-WREE)對小鼠AML-12正常肝細胞內DNA甲基化修飾酵素Dnmts蛋白質表現量之影響。 78 圖十四、 陳皮水萃後殘渣乙醇粗萃物(CP-WREE)對小鼠AML-12正常肝細胞內組蛋白乙醯化和甲基化修飾酵素蛋白質表現量之影響。 79 圖十五、 陳皮水萃後殘渣乙醇粗萃物 (CP-WREE) 對 APAP 誘導小鼠AML-12正常肝細胞損傷型態之影響。 80
圖十六、 CP-WREE經由活化Nrf2路徑和表觀遺傳學調控機制來保護乙醯胺基苯酚所誘導之肝損傷。 81
XII
附錄圖
附圖一、 人體肝臟位置 (Principles of Human Physiology Fifth Edition) 82
附圖二、 肝纖維化 83
附圖三、 肝臟第一/第二階段解毒代謝系統 (Clinical Nutrition: A Functional Approach Second Edition) 84
附圖四、 乙醯胺基苯酚之結構式 84
附圖五、 APAP在肝臟中的解毒代謝機制 85
附圖六、 APAP 產生MPT作用所誘導肝損傷之機制 85
附圖七、 細胞清除氧化劑之機制 86
附圖八、 Nrf2-AREs 抗氧化途徑 87
附圖九、 人參皂甙 Rb1活化Nrf2-AREs路徑 87
附圖十、 表觀遺傳學調控基因表現之機制 88
附圖十一、 DNA甲基化與影響基因表現 89
附圖十二、 組蛋白修飾作用 (Molecular Biology of the Cell Fifth Edition) 90
附圖十三、 組蛋白乙醯化修飾影響基因表現 91
附圖十四、 類黃酮衍生物之結 92
附圖十五、 HepG2-C8 細胞存活率測定之實驗流程圖 93
附圖十六、 ARE-Nrf2活性測定之實驗流程圖 93
附圖十七、 AML-12細胞存活率測定之實驗流程圖 94
附圖十八、 細胞內 mRNA、蛋白質與抗氧酵素系統分析之實驗流程圖 94
附圖十九、 中藥食材粗萃物與APAP共同處理細胞培養之實驗流程圖 95
附圖二十、 陳皮粗萃物 [(A) CP-WE, (B) CP-EE, (C) CP-WREE] 中多甲氧基黃酮類橘皮素(Tangeritin)、川陳皮素(Nobiletin)及4''-demethyltangeretin 之 HPLC 圖譜。 96

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