高血膽固醇濃度被認為與心血管疾病發生有密切的關係，許多研究
指出，statin類藥物可以降低血液膽固醇的。本實驗研究係探討添加
降血脂藥物lovastatin於不同蛋白質來源（黃豆蛋白或酪蛋白）中來比較lovastatin降低膽固醇的效果。以六週齡的雄性倉鼠40隻為實驗動物，分成四組為：酪蛋白組(對照組 )、酪蛋白+lovastatin組(實驗組)、黃豆蛋白組(對照組)、黃豆蛋白+ lovastatin組(實驗組)。為期四週的實驗，實驗期間採自由飲水、攝食的方式，飼養期間每週測量體重，飼養四週後犧牲。實驗結果顯示：倉鼠體重、組織重量各組無統計上差異。雖然lovastatin+酪蛋白組有偏低的血漿總膽固醇濃度，但四組間並沒有統計上差異。值得注意的是lovastatin的添加會明顯降低LDL+ VLDL-cholesterol濃度，但此種現象只在酪蛋白組發現。黃豆蛋白+ lovastatin組有明顯較低的血液三酸甘油脂濃度，然而酪蛋白+ lovastatin與酪蛋白組間則無統計上差異。有趣的是黃豆蛋白+ lovastatin組之肝臟三酸甘油酯含量明顯高於黃豆蛋白組。在糞便脂質則以黃豆蛋白組和黃豆蛋白+ lovastatin組其膽酸排出量有統計上差異( P< 0.05 )。綜合以上結果，推測lovastatin因不同蛋白質來源而有不同的降血酯效果。

According to the findings from existing studies of that statin can reduce bloody cholesterols related closely to cardiovascular diseases, the purpose of this study is to compare the effects on decreasing plasma lipids of lovastatin added in different protein sources- soy protein isolated (SPI) and casein. During the experimental period, 40 male hamsters in the age of 6 weeks were divided to 2 control groups (one was fed with SPI and the other was fed casein), and 2 experiment groups (one was fed with additional lovastatin in SPI, but the other was fed lovastatin combined with casein). Hamsters ingested food and water freely, as well as their weights were measured weekly for 4 weeks; then being the samples. The results indicated that statistic variation of the weight item of hamsters’ bodies and organic tissues in 4 groups were not found, except for the group feeding casein and lovastatin with lower concentrations of total plasma cholesterols. However, the concentrations of LDL (low density lipoprotein) and VLDL (very low density lipoprotein) cholesterols in the casein experimental group were decreased obviously. The SPI group showed apparently lower triglyceride concentration in blood than other groups, but no statistic variation was found in casein groups with or without lovastatin. About the triglyceride in liver, the SPI group with lovastatin had higher concentration than the simply ISP group. Furthermore, the excretion amount of bile acid in fecal lipid of SPI’s control and experiment groups were with statistically meaning (P<0.05). the effect of lovastatin on plasma lipids,may be dependent on the dietary protein sources.

目 錄
謝 誌 II
中文摘要 III
ABSTRACT IV
目 錄 VI
表目錄 IX
圖目錄 X
壹、研究背景 1
貳、文獻整理 3
一、高血脂症 3
二、高血脂症的治療與預防 4
三、食品蛋白質對於血脂質的影響 5
（一）飲食蛋白質種類對血脂質與脂蛋白代謝脂影響 6
（二）飲食蛋白質種類對肝臟脂質的影響 7
（三）飲食蛋白質種類對糞便固醇排出量的影響 7
（四）飲食蛋白質種類對脂肪酸組成的影響 8
（五）機制探討 9
（六）胺基酸的組成 10
四、 STATIN類降血脂藥物簡介 12
（一）作用機轉 14
（二）常見的副作用 15
儀器設備 16
實驗動物 17
實驗方法 17
（一）動物分組 17
（二）動物飼養及樣品收集 18
（三）血漿分析 18
( 四 )肝臟分析 21
( 五 )糞便分析 23
（六）統計方法 24
肆、實驗結果 25
一、實驗期間倉鼠體重的變化 25
二、臟器重量的變化 25
三、血漿脂質的變化 25
（一）總膽固醇(Total Cholesterol；TC)濃度變化 25
（二）三酸甘油酯(Triglyceride；TG)濃度變化 25
（四）血漿脂蛋白的脂質變化 26
（五）血漿TBARS (Thiobarbituric acid reactive substances)濃度的變化 26
（六）血漿中葡萄糖濃度變化 26
四、肝臟脂質的變化 27
（一）肝臟膽固醇含量的變化 27
（二）肝臟三酸甘油酯含量的變化 27
（三）肝臟磷脂質(Phospholipids；PL)濃度變化 27
（四）肝臟TBARS濃度的變化 27
（五）腎臟TBARS的濃度的變化 28
五、糞便脂質變化 28
（一）糞便膽固醇含量的變化 28
（二）三酸甘油酯 28
（三）糞便膽酸 28
伍、結果討論 29
一、不同蛋白質來源添加LOVASTATIN倉鼠生長與臟器重量變化 29
二、血漿脂質濃度的變化 29
1.總膽固醇、三酸甘油脂濃度變化 29
2.血漿脂蛋白的脂質變化 31
3.血漿中葡萄糖的變化 32
4.血漿TBARS ( Thiobarbituric acid reactive substances )的濃度變化化 33
三、肝臟脂質濃度的變化 33
1、肝臟膽固醇、三酸甘油酯濃度變化 33
2、肝臟TBARS的濃度變化 34
3、腎臟TBARS的濃度變化 35
陸、結論 37
實驗流程 44
柒、參考文獻 45
表目錄
表 一.飼料配方組成百分比（％） 38
表二.餵食不同蛋白質添加lovastatin的飼料四週後對倉鼠體重、組織重之影響 39
表三.餵食不同蛋白質添加lovastatin四週後對倉鼠血漿脂質含量之影響 40
表四.餵食不同蛋白質添加lovastatin四週後對倉鼠肝臟脂質含量之影響 41
表五.餵食不同蛋白質飼料添加lovastation 四週後對倉鼠糞便脂質及膽酸含量之影響 42
表六.餵食不同蛋白質添加lovastatin的飼料四週後對對倉鼠血漿及肝臟、 腎臟TBARS值影響 43

圖目錄
圖表 一. 餵食不同蛋白質飼料添加lovastatin四週後對倉鼠血漿中三酸甘油酯含量之影響 53
圖二.餵食不同蛋白質飼料添加lovastatin 四週後對血漿中血糖含量之影響 54
圖三餵食不同蛋白質飼料添加lovastatin 四週後對血漿中LDL+VLDL Cholesterol含量之影響 55
圖五.餵食不同蛋白質飼料添加lovastatin 四週後對倉鼠肝臟脂質TG含量之影響 57
圖六.餵食不同蛋白質飼料添加 lovastatin四週後對倉鼠糞便膽酸含量之影響 58
圖七.餵食不同蛋白質飼料添加 lovastatin四週後對倉鼠肝臟TBARS值影響 59


附表 一. ATP III Classification of LDL, Total, and HDL Cholesterol (mg/dL) national cholesterol education program (NCEP) adult treatment panel III (ATP III) 60
附表 二. Overview of lipoprotein transport pathways and fates 61
附表 三. HMG-COA reduced及Lovastain化學結構式 62
附表 四. 黃豆蛋白影響動物體內膽固醇濃度的可能途徑 63
附表 五. HMG-COA還原酶抑制劑抑制細胞生理功能的主要機轉 64

呂峰洲（1995）脂質過氧化作用之機轉、生理意義及其定量。自由基生物學與醫學3, p43-56,自由基雜誌社,臺北。
陳明豐 (1998) 高脂血症處置之新進展: 實症醫學的啟示。台北:台大醫院
內科學誌
曾春典（2004）心臟血管內科－自我診斷, pp35-51華城出版,臺北。
杜書卿；某醫學中心四種降血脂 Gemfibrozil, Lovaststin, Pravastatin, Acipimox之使用評估，國立成功大學臨床藥學研究所
碩士論文；指導教授：高雅慧陳建煒；民國八十五年七月
施議強，侯承佰，朱永譁，（2003）Statin降血脂藥物，台灣醫界，vol.46,NO.9 p25-29
張婉雅譯（2004）Katzung基礎與臨床藥理學, p591-594合記出版社,臺北
Adeli, K., Taghibiglou, C., Van Iderstine, S. C. & Lewis, G. F. (2001). Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Trends. Cardiovasc. Med, 11(5), 170-176.
Aebi, H. ( 1984 ). Catalase in vitro. Methods Enzymol, 105, 121-126.
Alladi, S., Gilbert, R., & Shanmugasundaram, K. R. (1989). Lipids, lipoproteins and lipolytic activity in plasma with dietary protein changes. Nitr Rep Int, 40, 653-661.
Auer J., Berent R., Weber T., & Eber B. (2002). Clinical significance of pleiotropic effects of statins: Lipid reduction and beyond. Curr Med Chem, 9, 1831-1850.
Baba,N., Radwan, H. & Itallie, T. V. (1992). Effects of casein versus soy protein diets on body composition and serum lipid levels in adult rats. Nutr Res, 12, 279-288.
Bereza, U. L., Brewer, G. J. & Hill, G. M. (1985). Effect of dietary cholesterol on erythrocyte peroxidant stress in vitro and in vivo. Biochim Biophys Acta, 835, 434-440.
Bergeron, N. & Jacques, H. (1989). Influence of fish protein as compared to casein and soy protein on serum and liver lipids, and serum lipoprotein cholesterol levels in the rabbits. Atherosclerosis 78, 113-121.
Bischoff, H. (1997). Cerivastatin: A novel synthetic and highly active HMG-CoA reductase inhibitor. Atherosclerosi ,135, 119-130.
Brenner,R.P. (1981). Nutritional and hormonal factors influencing desaturation of essential fatty acids. Prog Lipd Res, 20, 41-47.
Brinton, E. A., Eisenberg, S. & Breslow, J. L. (1990) A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates. J Clin Invest, 85, 144-151.
Bynen, A. C. (1990a). Comparisom of the mechanisms peoposed to explain the hypocholesterolemic effect of soybean protein versus casein in experimentl animals. J Nutr Sci Vitaminol, 36, s87-s93.
Bynen, A. C., West, C. E., Spaaij, C. J. K., Huisman, J., Leeuwen, P. V., Schutte, J. B. & Hackeng, W. H. L. (1990b). Cholesterol metabolism, digestion rates and postprandial changes in serum of seine fed purified diets containing either casein or soybean protein. J Nutr, 120, 422-430.
Carroll K. K., Huff M.W., & Roberts D. C. K. (1979). Vegetable protein and lipid metabolism. In H. L. Wilcke, D. T. Hopkins, & D. H. Waggle (Eds.), Soy protein and human nutrition (pp. 261-280). New York: Academic Press.
Chao. Y. S., Yamin, T. T. & Albert, A. W. (1982). Effects of cholestyramine on low density lipoprotein binding sites on liver membranes from rabbit with endogenous hypercholesterolemia induced by a whey starch-casein diet. J Biol Chem, 257, 3623-3627.
De Lorgeril, M., Salen, P., Martin, J. L., et al. (1999). Mediterranean diet, traditional risk factors, and the rate cardiovascular complications after myocardial infarction: Final report of the Lyon diet heart study. Circulation, 8, 843-864.
Denke, M.A. (1995). Cholesterol-lowering diets: A review of the evidence. Arch Intern Med, 155, 17-26.
Diane, K.W., Dianne, L.K., & Thomas, P.G. (1999). Prescribed use of cholersterol lowering drugs in the United States, 1978 through 1988. JAMA , 263, 2185-2188.
Dietschy, J. M., Turley, S. D. & Spady, D. K. (1993). Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animals species, including humans. J Lipid Res, 34, 1637-1659.
Folch, J., Less, M., & Sloane Stanley, G. H. (1957). A simple method for the isolation and purification of total lipids form animal tissue. J Biol Chem, 223, 497-509.
ForsytheⅢ, W.A. (1986). Dietary proteins, cholesterol and thyroxine: A proposed mechanesm. J Nutr Sci Vitaminol, 36, s101-s104.
Gabay, C., & Kushner, I. (1999). Acute-phase proteins and other systemic responses to inflammation. N Engl J Med, 340, 448-54.
Hemry, D. A., Cully, L. R., & Grigson, T., et al. (1991). Recent trends in the prescribing of cholesterol lowering drugs in Austrlia. Med J Aus, 155, 332-336.
Henwood, J. M., & Heel, R.C. (1988). Lovastatin: A preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. Drugs, 36, 429-54.
Hrabek-Smith, J. M., Kurowska, E. M., & Carroll, K. K. (1989). Effect of cholesterol-free, semipurified diets containing defferent levels of casein or soy protein on distribution of cholesterol and protein among serum lipoproteins of rabbits. Atherosclerosis, 76,125-130.
Huang, Y. S., Cunnane, S. C. & Horrobin, D. F. (1986). Effect of defferent dietary protein on plasma and liver fatty acid composition in growing rats. Pro Soc Exp Biol Med, 181, 399-403.
Igel, M., Sudhop, T., & Bergmann, K.V. (2002). Pharmacology of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins), including rosuvastatin and pitavastatin. J Clin Pharmacol, 42, 835-45.
Iritani, N., Suga, A., Fukuda, H., Katsurada, A. & Tanaka, T. (1988). Effects of dietary casein and soybean protein on triglyceride turnover in rats liver. J Nutr Sci Vitaminol, 34, 309-315.
Iritani, N., Inoguchi, K., Endo, M., Fukuda, E. & Morita, M. (1980). Identification of shellfish fatty acids and their effects on lipogenic enzymes. Biochim Biophys Acts, 618, 378-385.
Jove, M., Planavila, A., Cabrero, A., Novell, F., Ros, E., Zambon, D., Laguna, J. C., & Carrera, M. V. (2003). Reductions in plasma cholesterol levels after fenofibrate treatment are negatively correlated with resistin expression in human adipose tissue. Metabolism, 52, 351-355.
Khan, B. K., Wilcox, H. G. & Mcnamara, M. (1989). Cholesterol is require for secretion of very low density lipoprotein by rat liver. Biochem J, 258, 807-816.
Khosla, P., Samman, S., Carroll, K. K. & Huff, M. W. (1989). Turnover of I-VLDL and I-DL apolipoprotein B in rabbits fed diets containing casein or soy protein. Biochim Biophys Acta, 1002, 157-163.
Koba, K., Rozee, L. A., Horrobin, D. F. & Huang, Y. (1994). Effects of dietary protein and cholesterol on phosphatidylcholine and phosphatidylethanolamine molecular species in mouse liver. Lipids, 29, 33-39.
Kritchevsky, D. (1987). Vegetable protein and atherosclerosis. J Am Oil Chem Soc, 56, 135-140.
Kuyvenhoven, M. W., West, C. E. & Beynen, A. C. (1986). Fetal steroid excretion in relation to the development of casein-induced hypercholesterolemia in rabbit. J Nutr, 116, 1395-1404.
Laufs, U., Fata, L.V., Plutzky, J., & Liao, J. K. (1998). Upregulation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Circulation, 97, 1129-35.
Laufs, U., & Liao, J. K. (2000). Direct vascular: Effects of HMG-CoA reductase inhibitors. Trends Cardiovasc Med, 10, 143-148.
Lea, A. P., & Mc Tavish, D. (1997). Atorvastatin: A review of its pharmacological properties and therapeutic potential in the management of hyperlipidaemia. Drugs, 53, 828-47.
Liao, J. K. (2002). Beyond lipid lowering: The role of statins in vascular protection. Int J Cardiol, 86, 5-18.
Lutjohann, D., Sigit, J. I., Locatelli, S., Bergmann, V. K., & Schmidt, H. H. (2001). High-dose simvastatin (80mg/day) decreases plasma concentrations of total homocysteine in patient with hyperlipidaemia. Atherosclerosis, 155, 265-266.
Mc Tavish, D., & Sorkin, E. M. (1991). Pravastatin: A review of its pharmacological properties and therapeutic potential in hyperlipidaemia. Drugs, 42, 65-89.
Meeker, D. R., & Kesten, H. D. (1941). Effect of high protein diet on experimental atherosclerosis of rabbits. Arch Pathol, 31, 147-162.
Mokady, S. & Liener , I. E. (1982). Effect of plant on choleterol metabolism in growing rats fed atherogenic diets. Ann Nutr Metab, 26, 138-144.
Mokady, S., & Liener, I. E. (1982). Effect of plant proteins on cholesterol metabolism in growing rats fed atherogenic diets. Ann Nutr Metab, 25, 138-144.
Morrow, D. A., & Ridker, P. M. (2000). C-reactive protein, inflammation, and coronary risk. MedCli North Am, 84, 149-61.
Nagata, C., Takatsuka, N., Kurisu, Y., & Shimizu, H. (1998). Decreased serum total cholesterol concentration associated with high intake of soy products in Japanese men and women. J Nutr, 128, 209-213.
Nagata, Y., Ishiwaki, N., & Sugano, M. (1982). Studies on the mechanism of the antihypercholesterolemia action of soy protein and soy protein-type amino acid mixtures in relation to their casein counterparts in rats. J Nutr, 112, 1614-1625.
Nagata, Y., Tanaka, K., & Sugano, M. (1981). Further studies on the hypocholesterolemic effect of soybean protein in rats. Br J Nutr, 45, 233-241.
Nistor A, Bulla A, Filip DA, et al: The hyperlipidemic hamster as a model
of experimental atherosclerosis.　Atherosclerosis 68: 159-173, 1987.
Plosker, G. L., & Wagstaff, A.J. (1996). Fluvastatin: A review of its pharmacological propertiesand use in the management of hyperlipidaemia. Drugs, 51, 433-59.
Potter, S. M. (1995). Overview of proposed mechanisms for the hypocholesterolemic effect of soy. J Nutr, 125, 606s-611s.
Roach, A. E., Tsikouris, J. P., & Hasse, K. K. (2002). Rosuvastatin: A new HMG-CoA reductase inhibitors for hypercholesterolemia. Formulary, 37, 179-85.
Roberts, W. C. (1996). The underused miracle drugs: The statin drugs are to atherosclerosis what penicillin was to infectious disease. Am J Cardiol, 78, 377-378.
Sanchez, S., & Hubbard, R. W. (1989). Dietary protein modulation of serum cholesterol: The amino acid connection. In M. Friedman (Ed.), Vol. 3. Absorption and utilization of amino acids (pp. 247-273). Boca Raton, FL: CRC.
Sautier, C., Flament, C., Doucet, C., & Suquet, J. P. (1986). Effect of eight dietary proteins and their amino acid content on serum, hepaticand fecal steroids in the rat. Nutr Rep Int, 34, 1051-1059.
Sonmez, A., Baykal, Y., Kilic, M., Yilmaz, M. I., Saglam, K., Bulucu, F., & Kocar, I. H. (2003). Fluvastatin improves insulin resistance in nondiabetic dyslpidemic patients. Endocrine, 22, 151-154.
So Rell, R. (2001). Bacol withdraw from market. Circulation, 104, E9015-6.
Stein, E. A., Lane, M., & Laskarzewski, P. (1998). Comparison of statins in hypertriglyceridemia. Am J Cardiol, 81, 66-69.
Todd, P. A., & Goa, K. L. (1990). Simvastatin: A review of its pharmacological properties and therapeutic potential in hyperlipidaemia. Drugs, 40, 583-607.
Tracy, R. P. (1999). Inflammation marks and coronary heart disease. Curr Opin Lipidol 23, 236-241
Vaughan, C. J., Gotto, A. M. Jr, & Basson, C. T. (2000). The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol, 35, 1-10.
Werner, N., Nickenig, G., & Laufs, U. (2002). Pleiotropic effects of HMG-CoA reductase inhibitors. Basic Res Cardiol, 97, 105-116.