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研究生:戴宇昀
研究生(外文):Yu-Yun Dai
論文名稱:樟芝菌絲體與子實體對四氯化碳及酒精誘導之慢性及急性肝損傷之保肝功能評估
論文名稱(外文):Protective effects of the mycelium and sporocarp of Antrodia camphorata on chronic liver damage induced by CCl4 and ethanol-induced acute liver damage in vivo
指導教授:胡淼琳蔡金川蔡金川引用關係
指導教授(外文):Ml-Lin HuChin-Chuan Tsai
學位類別:碩士
校院名稱:國立中興大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:71
中文關鍵詞:樟芝抗氧化酵素四氯化碳肝損傷酒精
外文關鍵詞:Antrodia camphorataantioxidant enzymesCCl4Liver damageethanol
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樟芝Antrodia camphorata(原名 A. cinnamomea),僅生長在台灣特有的牛樟樹(Cinnamomum kanehirae)上,因其數量稀少,且久為民間所流傳之良好民俗偏方,遂成為台灣市場最昂貴的野生真菌。有鑑於肝病為我國之國病,久居國人十大死因之一,因此保肝之健康食品的開發實屬當務之急,故本論文之目的即在探討樟芝之保肝功效本。
本研究之第一部分係研究樟芝對CCl4所引起之肝傷害。其模式為以Wistar大鼠,分為A:control 組、B:CCl4組、C: CCl4+Silymarin組、D: CCl4+樟芝菌絲體低劑量組(1 g/kg)E: CCl4+樟芝菌絲體低劑量組(0.5 g/kg)共為期八週。40%CCl4劑量為0.3 ml/100g,每週兩次。試驗結果顯示A組之sGOT、sGPT於八週間皆顯著低於B、C、D、E組,此外除第一週外,B、C、D、E四組間之sGOT、sGPT皆隨著時間的增加而增加,且各組間無顯著差異,顯示C組(silymarin組)與兩組實驗組:D組(樟芝菌絲體低劑量組:0.5 g/kg b.w.)與E組(樟芝菌絲體高劑量組:1 g/kg b.w.)並不能有效的降低肝損傷時所造成的酵素脫逸,這個結果顯示樟芝能顯著降低CCl4所誘導的急性肝損傷,但不能顯著的降低多重CCl4所誘導的慢性肝傷害。此外包括抗氧化酵素(Catalase、SOD或GSH-Px)、TBARs值與8-OHdG/105dG含量的結果皆顯示:除了正常對照組的抗氧化酵素最高、TBARs值與8-OHdG/105dG含量最低外,其餘各組間則無差異。另外由肝組織切片所進行的毒理觀察亦與生化值、各種傷害指標吻合,表示包括silymarin與低、高劑量樟芝菌絲體於此模式下並未能達顯著的保護效果。
若將silymarin的劑量提高為200 mg/kg,並將40﹪CCl4劑量由原來的0.3 ml/100g降低為0.1 ml/100g,投與方式由皮下注射(s.c.)改為腹腔注射(i.p.)則可以顯著改善其對於CCl4所誘導的慢性肝損傷,較適於新模式之探討。
樟芝傳統療效中,有解酒、酒宿醉的功能,本研究第二部分以樟芝菌絲體與野生棌摘樟芝子實體為材料,進行急性酒精性肝損傷保肝功能之評估。Wistar大鼠(180~200 g),分為正常組(0.9% NaCl)、肝損傷組、silymarin處理組(200 mg/kg)、樟芝菌絲體與子實體之低(0.5 g/kg)、高(1 g/kg)劑量、僅管餵樟芝菌絲體高劑量(1 g/kg)組等八組。結果顯示酒精的投予會造成肝損傷組sGOT與sGPT指數顯著高於正常組(p<0.01),而樟芝菌絲體低(0.5 g/kg)、高(1 g/kg)劑量、樟芝子實體低(0.5 g/kg)、高(1 g/kg)劑量組,就sGOT治療效果而言,有隨劑量的升高而得到較好的保護效果,而sGPT則無。至於BUN與CRE這兩個腎傷害生化指標方面,本研究發現各組間皆無顯著性的差異,表示酒精的注射不會造成腎絲球的的傷害。抗氧化酵素方面:Catalase與SOD活性於酒精處理組為最高,GSH-Px則於各組間無顯著差異(p>0.05),此結果暗示酒精代謝過程中,會誘導肝臟SOD及catalase基因的表現,加速自由基的排除。而樟芝菌絲體與子實體之低、高劑量組則具有抑制酒精代謝時所伴隨的抗氧化酵素升高之現象,此結果暗示樟芝具有不錯的抗氧化效果。TBARs值與H.E. stain切片染色結果亦顯示:樟芝菌絲體與子實體之低、高劑量組則能顯著降低脂質過氧化與改善酒精處理所產生的病理狀況,其改善效果則有劑量上的關係。
因此,經現代科學分析與研究,證實樟芝菌絲體與子實體不論低或高劑量,確有降低酒精所誘發之急性肝損傷之功能,其保護效果有劑量上的關係,而保護機制上,與樟芝本身所具有的抗氧化與清除自由基能力有關。
Antrodia camphorata is a well-known fungus that only grows on Cinnamomum kanehirae, a unique plant only found in Taiwan with limited quantity. It is believed that Antrodia camphorata can provide several effective cure abilities, including detoxification, anticancer, and protection against alcohol-induced liver diseases. Thus it has become the most valuable fungus in Taiwan. About 15%∼20% population in Taiwan have liver diseases and every year it takes approximately five thousands people’s lives by liver cancer and four thousands by liver sclerosis and liver disease is known as “country-disease”. Therefore it is important to develop health food, especial native, unique materials, such as Antrodia camphorata in Taiwan for prevention and cure of liver disease.
The aim of this study was to investigate whether Antrodia camphorata is a good remedy for liver damage. In the first part of chapter one, we used CCl4 to induce chronic liver damage in rats. Sixth Wistar rats were divided into five groups: Control, CCl4(negative control), CCl4+25 mg/kg silymarin(positive control), CCl4+0.5 g/kg mycelium of Antrodia camphorata , CCl4+1 g/kg mycelium of Antrodia camphorata. CCl4 was given twice a week at a dose of 0.3 ml/kg of 40% CCl4 for 8 weeks.
In the first week, Antrodia camphorata and silymarin significantly reduced the increasing sGOT and sGPT activities induced by CCl4, but it made no different on the levels of sGOT and sGPT among groups of CCl4, silymarin, low and high dose Antrodia camphorata during 2∼8 weeks. The results reflected that Antrodia camphorata had the ability to eliminate acute liver damage by CCl4, but had no significant effect on chronic CCl4- induced damage. Furthermore, the results of antioxidant enzymes activities(catalase, SOD, glutathione peroxidase), lipid peroxidation, 8-hydroxy-2’-deoxyguanosine and H.E. stain, showed that except the animals of control group, there are no significant different among groups of CCl4, silymarin, low and high dose Antrodia camphorata. These phenomena were consist with the levels of sGOT and sGPT, and were confirmed by histopathologic observation. Combination the results mentioned above, we concluded that including silymarin , low and high dose of Antrodia camphorata showed no significant effect to protect chronic liver damage in the model of multiple CCl4-intoxication.
In order to determine model of multiple CCl4-intoxication for practical assays on the ability of protecting liver damage, we used a new model by raising the dose of silymarin from 25 mg/kg to 200 mg/kg, decreasing the dose of CCl4 from 0.3 ml/kg to 0.1 ml/kg, and changing the method of CCl4 injection. In this new model, serum activities of GOT and GPT of silymarin at dose of 200 mg/kg significantly decreased the damage induced by CCl4 at the third week, and kept lower than CCl4-intoxication group at sixth week. Silymarin also exhibited antioxidant effect on decreasing lipid peroxidation, it significantly decreased the TBARs induced by CCl4. Histopathologic profile showed that silymarin had better morphology structure, less pathology symptom of liver damage. The results demonstrate it could be a better and practical model of assaying the abilities of hepatoprotection.
In the second part, rats were orally administrated with mycelium and sporocarp of Antrodia camphorata for ten days before ethanol challenge. The results showed that mycelium and sporocarp of Antrodia camphorata had perfect effect to protect acute liver damage induced by ethanol(20 %). Both low(0.5 g/kg)and high(1 g/kg)doses of mycelium and sporocarp of Antrodia camphorata significantly decreased the levels of sGOT and sGPT by 31.3﹪∼44.7﹪and 32.5﹪∼38.7﹪; of lipid peroxidation by 73.7﹪∼84.2﹪. In this model, SOD and catalase activities were increased compensatively while oxidative stress were processing during ethanol metabolism and mycelium consistent with sporocarp could significantly decrease the activities of antioxidant enzymes(except GSH-Px)induced by ethanol. From the views of hepatic and kidney histopathology slices (H.E. stain), it reveled that, CCl4+low(0.5 g/kg)and high(1 g/kg)dose of mycelium and sporocarp of Antrodia camphorata certainly protected against lipid vacuolation accumulation and hydropic degeneration of hepatocyte; and against the loss of cellular boundaries, necrosis of cell of proximal tubular, and the accumulation of globules of protein debris in the tubular lumens of renal cells. It was interesting to connect the results of sGOT, protein carbonyl group, and histopathologic observation, we concluded that effect of hepatoprotection of mycelium and sporocarp of Antrodia camphorata exhibited a dose-dependent relation. All the biology and physiology profiles of group with only oral administration of mycelium of Antrodia camphorata for ten days without ethanol treatment remained normally, and in some test, it even had lower level than normal control. These results indicated that mycelium of Antrodia camphorata is a low toxicity substance and may provide some physiology activities.
In summary, although there were no significant effects for the mycelium of Antrodia camphorata to protect chronic liver damage in rats injected with CCl4 in the model mentioned above, the mycelium and sporocarp of Antrodia camphorata indeed showed good ability to protect acute liver damage induced by ethanol. We hope to investigate its effect on the chronic ethanol-induced in the future, so it could be close to the practical and clinical use.
目錄(第一章 第一部份)
前言……………………………………………………………………………..……2
一. 肝病………………………………………………..……………………...…2
二. 樟芝(Antrodia camphorata)…………………………………………..…2
※樟芝子實體與深層發酵之菌絲體之照片……………………………………3
三. Silymarin……………………………………………….……………..….….4
四. CCl4(Carbon tetrachloride)……………………………………...…..…4
※ 四氯化碳至慢性肝損傷機制…………………………………..……...6
實驗動機與目的…………………………………………………………………….7
材料與方法………………………………………………………………………….7
(一)材料………………………………………………………………………….7
(二)方法………………………………………………………………………….8
1. 樟芝之急毒性試驗………………………………………………….……8
※ 劑量範圍之選定…………………………………………………….…8
※ 配製及餵食法………………………………………………….………8
2. 樟芝菌絲體對四氯化碳所誘發慢性肝炎之in vivo試驗………………8
2.1.1 劑量選取……………………………………………………….…..8
2.1.2 實驗設計………………………………………………….………..9
2.2 實驗流程…………………………………………………………....9
3. 1大鼠體重變化情形……………………………………………………..10
3.2大鼠肝、腎臟絕對與相對重量變化…………………………………...10
4. 肝功能生化指數的檢測…………………………………………...……..10
5. 蛋白質含量的測定……………………………………………...………..10
6. TSH 和NPSH 的測定…………………………………………………..10
7. 肝臟中抗氧化酵素之測定………………………………………….…...10
7.1 Catalase……………………………………………………………….10
7.2 SOD……………………………………………………………….….11
7.3 GSH peroxidase……………………………………………….…..….11
8. 脂質過氧化……………………………………………………..……..…11
9. 8-OH-dG含量之測定………………………………………………..…..11
10.組織病理學的觀察……………………………………………………...11
11.統計分析…………………………………………………………….…..12
結果與討論…………………………………………………………………………12
(一)樟芝王安全性評估(ICR小鼠急毒性試驗)……………………………….12
(二)樟芝對四氯化碳所誘發慢性肝炎之in vivo試驗………………………12
一.外在觀察…………………………………………………………………12
二.生化值……………………………………………………………………12
三.大鼠體重變化……………………………………………………………13
四.樟芝菌絲體對大鼠器官絕對與相對重量之影響………………………13
五. 樟芝王對肝臟中TSH(total thiol groups)與NPSH(non-protein thiol
groups)含量之影響………………………………………………….…13
六. 抗氧化酵素之變化………………………………………………………13
七. TBARs……………………………………………………………………13
八. 8-OHdG/105dG…………………………………………………………..14
九. 組織切片H.E.染色………………………………………………………14
結論………………………………………………………………………………..14
圖表目錄(第一章 第一部份)
(圖一)四氯化碳誘發肝損傷機制圖…………………………………………...…..6
(表一)樟芝菌絲體安全性評估(ICR小鼠急毒性試驗)…………………………15
(表二)管餵樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之大鼠肝、腎之絕對及相對重量之影響…………………………………………………………………16
(表三)管餵樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之大鼠肝中
之TSH(total thiol groups)與NPSH(non-protein thiol groups)含量影響…...17
(圖二)管餵樟芝菌絲體對四氯化碳誘發慢性肝損傷之大鼠體重之影響……….18
(圖三)管餵樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之第一週(上圖)、第三週(下圖)血清GOT、GPT含量的影響……………………………………19
(圖四)管餵樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之第四週(上圖)
六週(下圖)血清GOT、GPT含量的影響………………………………………20
(圖五)管餵樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之第八週血清GOT、GPT含量的影響…………………………………………………………….21
(圖六)管餵樟芝菌絲體對皮下注射四氯化碳誘導慢性肝損傷之血清GOT、GPT
八週趨勢圖…………………………………………………………………………..22
(圖七)樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之大鼠肝中抗氧化酵素之影響…………………………………………………………………………………..23
(圖八)樟芝菌絲體對皮下注射四氯化碳誘發慢性肝損傷之大鼠肝中脂質過氧化與8OHdG/105dG含量之影響…………………………………………………………24
(圖九)正常組(A組)與酒精處理組(B組)之肝臟H.E.切片染色……..……..25
(圖十)Silymarin組(C組)與樟芝菌絲體低劑量組(D組)之肝臟
H.E.切片染色…………………………………………………………………...26
(圖十一)樟芝菌絲體低劑量組(D組)之肝臟H.E.切片染色…………..……….27
目錄(第一章 第二部份)
一. 實驗動機與目的……………………………………………………………..29
二. 材料與方法…………………………………………………………………..29
※ 試驗方法流程………….………………………………………………..29
三. 結果與討論…………………………………………………………………..29
(一)生化值…………………………………………………………………29
(二)TBARs值……………………………………………………………..30
(三)8-OHdG/105dG含量…………………………………………………..30
(四)TSH(Total SH-group)與NPSH(Glutathione)含量……………..30
(五)四氯化碳處理組之脂質過氧化值與8-OHdG/105dG含量之相關性..30
(六)肝組織切片染色………………………………………………………..31
四. 結論…………………………………………………………………………….31
圖表…………………………………………………………………………………32
參考文獻……………………………………………………………………………38
圖表目錄(第一章 第二部份)
(表四)200 mg/kg之Silymarin 對四氯化碳誘發慢性肝損傷之TSH值與NPSH含量之影響…………………………………………………………………………….32
(圖十二)Silymarin(200mg/kg, p.o.)對四氯化碳誘發慢性肝損傷之第一、三、六週血清GOT、GPT之影響………………………………………………………..33
(圖十三)Silymarin(200mg/kg, p.o.)對四氯化碳誘發慢性肝損傷之TBARs值與8-OHdG/105dG含量之影響………………………………………………………34
(圖十四)四氯化碳誘發慢性肝損傷之TBARs值與8-OHdG/105dG含量之相關性……………………………………………………………………………………..35
(圖十五)正常組(A組)與四氯化碳處理組(B組)之肝臟H.E.切片染色...36
(圖十六)Silymarin 組之肝臟H.E.切片染色.……………………………………37
目錄(第二章)
前言…..……………………………………………………………………………..43
動機與目的……..…………………………………………………………………..43
材料與方法………..………………………………………………………………..43
(一) 材料……………………………………………………………………….43
(二) 方法……………………………………………………………………….45
1. 大鼠體重變化情形……………………………………………………..45
2. 大鼠肝、腎臟絕對與相對重量變化…….…………………………….45
3. 肝、腎生化指數的檢測………………………………………………..45
4. 蛋白質含量的測定……………………………………………………..45
5. TSH 和NPSH 的測定…………………………………………………45
6. 肝臟中抗氧化酵素之測定………………...…………………………...45
6.1 Catalase………………………………..……………………………45
6.2 SOD……………………………………...………………………….46
6.3 GSH peroxidase………………………………………...…………...46
7.脂質過氧化……………………………………………..…….…………46
8.蛋白質Carbonyl group 分析…………………………….….…………46
9. 8-OH-dG含量之測定………………………………………..………...46
10.組織病理學的觀察…………………………………………………...47
11.統計分析………………………………………………………………47
結果與討論………………………………………………………………………….47
1. 1肝、腎組織的的外在觀察……………………………………………………47
1. 2肝、腎的絕對與相對重量…………………………………………………….47
2.生化值…………………………………………………………………………...47
3.肝臟之TSH與GSH…………………………………………………………….48
4.肝臟之抗氧化酵素變化………………………………………………………...48
5.肝臟之脂質過氧化…………………………………………………………...…48
6.肝臟之蛋白質Carbonyl group………………………………………………….48
7.肝臟之8-OHdG/105dG………………………………………………………….48
8.H.E.組織切片染色………………………………………………………………48
8.1肝臟………….………………………………………………...……………49
8.2腎臟…………………………………………………………………………49
總結………………………………………………………………………………….50
圖表………………………………………………………………………………….51
參考文獻…………………………………………………………………………….68
圖表目錄(第二章)
(表一)樟芝對酒精腹腔注射誘發大鼠急性損傷之器官絕對重量之影響……51
(表二)樟芝對酒精腹腔注射誘發大鼠急性損傷之器官相對重量之影響……52
(表三)樟芝對酒精腹腔注射誘發大鼠急性損傷之肝臟中TSH(total thiol groups)、NPSH(non-protein thiol groups)含量之影響……………………….53
(圖一)管餵樟芝菌絲體與子實體對酒精誘發急性損傷之血清GOT、GPT含量的影響……………………………………………………………………………..54
(圖二)管餵樟芝菌絲體與子實體對酒精腹腔注射誘發急性損傷之血清BUN、CRE含量的影響………………………………………………………………….55
(圖三)管餵樟芝菌絲體與子實體對酒精腹腔注射誘發急性損傷之血清Glu含量的影響…………………………………………………………………………….56
(圖四)管餵樟芝菌絲體、子實體對酒精腹腔注射誘發急性損傷之抗氧化酵素變化………………………………………………………………………………….57
(圖五)管餵樟芝菌絲體、子實體對酒精腹腔注射誘發急性損傷之脂質過氧化變化…………………………………………………………………………………58
(圖六)管餵樟芝菌絲體、子實體對酒精腹腔注射誘發急性損傷之蛋白質Carbonyl group含量變化…………………………………………………………………..59
(圖七)正常組(A組)與酒精處理組(B組)之肝臟H.E.切片染色………..60
(圖八)Silymarin組(C組)與樟芝菌絲體低劑量組(D組)之肝臟H.E.切片染色…………………………………………………………………………………61
(圖九)樟芝菌絲體高劑量組(E組)與樟芝子實體低劑量組(F組)之肝臟H.E.切片染色……………………………………………………………………..62
(圖十)樟芝子實體高劑量組(G組)與僅樟芝菌絲體高劑量組(H組)之肝臟H.E切片.染色…………………………………………………………………….63
(圖十一)正常組(A組)與酒精處理組(B組)之腎臟H.E.切片染色……..64
(圖十二)Silymarin組(C組)與樟芝菌絲體低劑量組(D組)之腎臟H.E.切片染色……………………………………………………………………………..65
(圖十三)樟芝菌絲體高劑量組(E組)與樟芝子實體低劑量組(F組)之腎臟H.E.切片染色……………………………………………………………………66
(圖十四)樟芝子實體高劑量組(G組)與僅樟芝菌絲體高劑量組(H組)之腎臟H.E.切片染色…………………………………………………………………67
參考文獻…………………………………………………………………………..68
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