牛樟芝（Antrodia camphorata; niu-chang-chih）又稱樟芝或牛樟菇，為本省特有種真菌，僅生長於老齡牛樟樹（Cinnamomum kanehirai Hay），為一本土性非常具有經濟效益的保健食品材料。然而，過去實驗多直接以牛樟芝之菌絲體、子實體、發酵液或發酵液乾燥物等為實驗材料，對於不同極性區分萃出物之生理活性之探討相當有限。本實驗利用水、乙醇、乙酸乙酯與乙醚等不同極性之溶劑萃取牛樟芝發酵液，經減壓濃縮與冷凍乾燥後，將此等不同極性萃出物作為實驗材料，配合大鼠灌食之實驗模式，探討它們對大鼠肝臟抗氧化與藥物代謝酵素活性與表現之影響。實驗結果發現，灌食七週後，大鼠之最終體重或肝臟、腎臟與脾臟對體重之相對重量比均與控制組無顯著性差異；肝臟還原型glutathione (GSH)及總GSH濃度則是25或100 mg/kg BW乙醇萃出物以及5 mg/kg BW乙酸乙酯和乙醚萃出物灌食組皆顯著低於控制組（p <0.05）；在GSH相關抗氧化酵素及超氧歧化酶活性（SOD）方面，各灌食組與控制組相較下，glutathione-S-transferase（GST）、glutathione reductase（GRd）與glutathione peroxidase（GPx）之酵素活性無顯著差異，而在SOD活性方面，除了5及25 mg/kg乙醚萃出物及5 mg/kg乙酸乙酯萃出物與對照組無差異外，其餘灌食組中肝臟SOD活性皆明顯高於控制組（p＜0.05）。進一步分析肝臟內生性或以TBH或以FeSO4誘發之thiobarbituric acid-reactive substances濃度，各牛樟芝發酵液萃出物處理組也與控制組無顯著性差異。在肝臟之藥物代謝酵素活性與蛋白表現方面，各灌食組間ethroxyresorufin O-deethylase (EROD), 7-pentoxyresorufin O-dealkylase (PROD), N-nitrosodimethylamine demethylase (NDMAD), and erythromycin demethylase (EMD)之活性皆與控制組無顯著性差異；但西方免疫墨點法分析卻顯示各種萃出物處理組的CYP 1A1與型GSH S-transferase (PGST)之蛋白表現量較對照組高；至於cytochrome P450 (CYP) 2B1, 2E1, 和 3A1之蛋白質表現所得結果亦與酵素活性相似，各組間並無差異。
由上述實驗結果可知，不同極性萃出物灌食大鼠雖減少肝臟GSH含量，但適當濃度之水、乙醇與乙酸乙酯抽出物則可增加肝臟SOD活性，也不會影響大鼠肝臟中脂質過氧化作用；藥物代謝酵素方面，只有CYP 1A1與PGST蛋白表現受到牛樟芝發酵液萃出物的影響，且四種不同極性萃出物均可增加其表現，顯示牛樟芝發酵液含有調控肝臟藥物代謝酵素表現之成份，且此類成分應可存在不同極性區分中。

Antrodia Camphorata（Niu-chang-chih）is a local fungi specie found in Taiwan. It seems to only grow on elder Niu-chang tree（Cinnamomum Kanehirai Hay）. Based on various reports, Antrodia Camphorata has been regarded as a function food. In previous studies, the mycelium, fruit body, mycelium fermentative extracts of Antrodia Camphorata（MFEAC）have been used as experimental materials to investigate whether Antrodia Camphorata owns health-improved physiological activities. Among those Antrodia Camphorata products, MFEAC and its possible active components is much less studied as compared with the mycelium and fruit body. In this study, solvents with various polarity including water, ethanol, ethyl acetate and ether were used to extract the MFEAC. Following vacuum-condensation and freeze-dry of these solvent extracts, male Sprrague-Dawley rats were orally administered 25 or 100 mg/kg water and ethanol extracts or 5 or 25 mg/kg ethyl acetate and ether extract four times a week for seven weeks. The control rats received ddH2O only. At the end of experimentation, the final body weight and the relative weight of liver, kidney and spleen are not affected by the administration of those four different solvent extracts of MEFAC in either low or high dose. GSH and total GSH levels, however, were significantly lower in rats treated with 25 or 100 mg/kg ether extracts, or in rats dosed with 5 mg/kg ethyl acetate or ether extracts as compared to the control（p＜0.05）. Regarding to the antioxidant system, hepatic glutathione（GSH）peroxidase and GSH reductase activities were similar between each treated and control groups, but hepatic SOD activity was significantly higher in rats treated with 25 or 100 mg/kg water or ethanol extracts or 25 mg/kg ethyl acetate（p＜0.05）as compared to control rats. The endogenous TBARS level or TBH- or FeSO4- induced TBARS production were not changed by either solvent extracts. Hepatic ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, N-nitrodimethylamine demethylase and erythromycin demethylase activities and also the expression level of cytochrome P450（CYP）2B1, 2E1and 3A1 were not changed by those solvent extract of MFEAC. In contrast, regardless of the solvents used, CYP 1A1 level was noted to increase in rats treated with either one of the MFEAC extracts as compared to the control rats. Moreover, protein level of the π form of GSH S-transferase was also higher in the MFEAC extract treated rats than the controls.
Thease results suggested that the solvent extract of MFEAC may increase hepatic SOD activity but decrease GSH content, and may not change the lipid peroxidation in livers. Moreover, the solvent extracts of MFEAC increase the expression of CYP 1A1 and PGST, it shows MFEAC contains biologically active components that can alive in various organic solvent extracts of MFEAC.

摘要
文獻探討…………………………………………………………… 1
一、牛樟芝………………………………………………………… 1
二、自由基………………………………………………………… 6
三、肝臟…………………………………………………………… 10
四、生物轉換酵素系統…………………………………………… 12
細胞色素P450……………………………………………………………17
麩胱甘肽硫轉移酶………………………………………………………29
實驗動機…………………………………………………………………36
材料與方法………………………………………………………………37
一、實驗材料……………………………………………………………37
（一）實驗動物…………………………………………………………37
（二）樟芝菌絲體發酵過濾液之製備…………………………………37
（三）藥品試劑…………………………………………………………37
二、實驗方法……………………………………………………………41
（一）動物飼養…………………………………………………………41
（二）實驗項目分析……………………………………………………41
1.細胞質/微粒體製備…………………………………………………41
2.蛋白質濃度測定………………………………………………………42
（2.1）Lowry et al., 1951…………………………………………42
（2.2）Bio-Rad Protein Assay kits………………………………42
3.GSH濃度與抗氧化酵素活性分析……………………………………42
（一）肝臟還原態麩胱甘肽（GSH）及氧化態麩胱甘肽分析
（GSSG）………………………………………………………………42
【GSH與GSSG標準曲線之製備】………………………………… 43
【HPLC條件】…………………………………………………………43
（二）紅血球還原態麩胱甘肽（GSH）及氧化態麩胱甘肽分析
（GSSG）………………………………………………………………44
（三）麩胱甘肽轉移酶活性測定……………………………………44
（四）麩胱甘肽過氧化酶活性測定…………………………………45
（五）麩胱甘肽還原酶活性測定……………………………………47
（六）超氧歧化酶活性測定…………………………………………47
4.CYP酵素活性測定…………………………………………………48
（一）Pentoxyresorufin O-depentylase（PROD）activity
分析……………………………………………………………48
（二）Ethroxyresorufin O-deethylase（EROD）activity
分析……………………………………………………………49
（三）N-nitrosodimethylamine demethylase（NDMAD）
activity分析…………………………………………………………50
（四）Erythromycin demethylase（EMD）activity
分析……………………………………………………………51
5.血漿中蛋白質硫醇（plasma protein thiol , PSH）含量分析……………… 51
6.肝臟脂質過氧化物（TBARS）分析…………………………………52
7.FeSO4或tert-butyl hydroperoxide（TBH）誘發肝臟脂
質過氧化物（TBARS）分析……………………………………………53
8.西方點墨法（Western blotting）………………………………54
三、統計分析…………………………………………………………56
結果……………………………………………………………………57
一、牛樟芝菌絲體發酵萃取液之水、乙醇、乙酸乙酯與乙醚
萃出物之製備率………………………………………………………57
二、牛樟芝菌絲體發酵液之不同極性有機溶劑萃出物對大鼠
體重及其臟器重量與相對臟器重之影響……………………………57
三、牛樟芝菌絲體發酵液萃出物對大鼠肝臟與紅血球中還原
態麩胱甘肽（GSH）含量之影響……………………………………57
四、牛樟芝發酵液萃出物對大鼠肝臟GSH相關抗氧化酵素及
超氧歧化酶活性之影響………………………………………………58
五、內生性或FeSO4或tert-butyl hydroperoxide (TBH)處理下，
不同極性牛樟芝發酵液萃出物對大鼠肝臟均質液脂質過氧
化作用之影響…………………………………………………………58
六、不同極性牛樟芝發酵液萃出物對大鼠肝臟生物轉換酵素活
性之影響………………………………………………………………59
七、不同極性牛樟芝發酵液萃出物對大鼠肝臟生物轉換酵素蛋
白質表現之影響………………………………………………………59
八、不同極性牛樟芝發酵液萃出物對大鼠血漿中protein thiol
（PSH）含量之影響…………………………………………………59
結果圖表………………………………………………………………60
討論……………………………………………………………………71
結論……………………………………………………………………75
參考文獻………………………………………………………………76
文獻回顧表次
表一、各種與代謝xenobiotics有關的酵素…………………………………… 13
表二、各種哺乳類動物的CYP酵素及其相對應的受質種類…………27
表三、多種細胞核內接受器調節CYPs的誘發作用…………………28
表四、Nuclear receptor的內生性配體和DNA上的反應區…………28
結果表次
頁次
表一、牛樟芝發酵液以不同極性之溶劑之萃取率……………………60
表二、飲食成分表………………………………………………………61
表三、不同極性牛樟芝發酵液萃出物對大鼠體重及臟器重量之
影響……………………………………………………………………62
表四、不同極性牛樟芝發酵液萃出物對大鼠臟器相對重量之影
響………………………………………………………………………63
表五、不同極性牛樟芝發酵液萃出物對大鼠肝臟glutathione
(GSH)濃度之影響……………………………………………………64
表六、不同極性牛樟芝發酵液萃出物對大鼠肝臟抗氧化酵素活
性之影響………………………………………………………………65
表七、不同極性牛樟芝發酵液萃出物對大鼠肝臟均質液在氧化劑
誘發下脂質過氧化之影響……………………………………………66
表八、不同極性牛樟芝發酵液萃出物對大鼠肝臟細胞色素P450
解毒代謝酵素活性之影響……………………………………………67
文獻回顧圖次
頁次
圖一、牛樟芝………………………………………………………………5
圖二、自由基誘發細胞凋亡之過程………………………………………9
圖三、各種生物轉換作用步驟……………………………………………13
圖四、外來化學物質和內生性荷爾蒙對CYP基因的誘發作用…………24
圖五、細胞色素P450的系統分類…………………………………………24
圖六、細胞色素P450的催化作用…………………………………………25
圖七、細胞色素P450 BM3的概要結構……………………………………26
圖八、細胞色素P450的受質種類…………………………………………26
圖九、GSH反應相關酵素…………………………………………………30
圖十、GST抑制JNK訊息傳遞的模式………………………………………35
結果圖次
頁次
圖一、不同極性牛樟芝發酵液萃出物對大鼠紅血球GSH濃度
之影響…………………………………………………………………68
圖二、不同極性牛樟芝發酵液萃出物對大鼠肝臟生物轉換酵素
蛋白質表現之影響……………………………………………………69
圖三、不同極性牛樟芝發酵液萃出物對大鼠血漿中蛋白質硫醇
（PSH）含量之影響…………………………………………………70

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