請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27150完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 何?芳 | |
| dc.contributor.author | Chia-Chun Lin | en |
| dc.contributor.author | 林嘉均 | zh_TW |
| dc.date.accessioned | 2021-06-12T17:56:32Z | - |
| dc.date.available | 2010-02-20 | |
| dc.date.copyright | 2008-02-20 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-01-30 | |
| dc.identifier.citation | 陳志堯, 薛又仁, 顏宗賢 and 邱俊杰譯 (2002) 抗癌藥物, 最新圖解藥理學, pp 378-380. 合記書局, 台北市.
薛偉承 (2006) St. John's wort對大鼠腸道及肝臟Cytochrome P450活性之影響；指導教授：何蕴芳 助理教授, 藥學研究所, 國立臺灣大學 Baccanari D., Phillips A., Smith S., Sinski D. and Burchall J. (1975) Purification and properties of Escherichia coli dihydrofolate reductase. Biochemistry 14, 5267-5273. Barr W. H. and Riegelman S. (1970) Intestinal drug absorption and metabolism. I. Comparison of methods and models to study physiological factors of in vitro and in vivo intestinal absorption. J Pharm Sci 59, 154-163. Bertino J. R., Perkins J. P. and Johns D. G. (1965) Purification and properties of dihydrofolate reductase from Ehrlich acsites carcinomacells. Biochemistry 4, 839-846. Blau N. and Burgard P. (2006) Disorders of phenylalanine and tetrahydrobiopterin metabolism, in Physician’s Guide to the Treatment and Follow-Up of Metabolic Diseases (Blau N., Hoffmann G. F., Leonard J. and Clarke J. T. R., eds), pp 25-34, New York. Blau N., Bonafe L. and Thony B. (2001) Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of DOPA-responsive dystonia and sepiapterin reductase deficiency. Mol. Genet. Metab. 74, 172-185. Bonafe L., Thony B., Leimbacher W., Kierat L. and Blau N. (2001) Diagnosis of Dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin. Chem. 47, 477-485. Bradford M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254. Choi H. J., Lee S. Y., Cho Y., No H., Kim S. W. and Hwang O. (2006) Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: Implications for Parkinson's disease. Neurochem. Int. 48, 255-262. DA S., DM W. and FJ H. (1997) Application of statistics to datatreatment and evaluation, in Fundamentals of Analytical Chemistry, pp 47-70. Harcourt Brace Coolege, Orlando, Florida, USA. Dams T. and Jaenicke R. (2001) Dihydrofolate reductase from Thermotoga maritima. Meth. Enzymol. 331, 305-317. David H. (1980) Methodological problems and results of the volume and surface determination of rat liver cells during postnatal development. Gegenbaurs Morphol Jahrb 126, 285-292. DeSesso J. M. and Jacobson C. F. (2001) Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. Food Chem. Toxicol. 39, 209-228. Fasco M. J., Silkworth J. B., Dunbar D. A. and Kaminsky L. S. (1993) Rat small intestinal cytochromes P450 probed by warfarin metabolism. Mol. Pharmacol. 43, 226-233. Fiege B., Ballhausen D., Kierat L., Leimbacher W., Goriounov D., Schircks B., Thony B. and Blau N. (2004) Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. Mol. Genet. Metab. 81, 45-51. Forrester J. M. (1972) The number of villi in rat's jejunum and ileum: effect of normal growth, partial enterectomy, and tube feeding. J Anat 111, 283-291. Friedkin M., Crawford E., Humphreys S. R. and Goldin A. (1962) The association of increased dihydrofolate reductase with amethopterin resistance in mouse leukemia. Cancer Res. 22, 600-606. Fukushima T. and Nixon J. C. (1980) Analysis of reduced forms of biopterin in biological tissues and fluids. Anal. Biochem. 102, 176-188. Gorren A. C. F. and Mayer B. (2002) Tetrahydrobiopterin in nitric oxide synthesis: a novel biological role for pteridines. Curr. Drug Metab. 3, 133-157. Harada T., Kagamiyama H. and Hatakeyama K. (1993) Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity. Science 260, 1507-1510. Harding C. O., Neff M., Wild K., Jones K., Elzaouk L., Thony B. and Milstien S. (2004) The fate of intravenously administered tetrahydrobiopterin and its implications for heterologous gene therapy of phenylketonuria. Mol. Genet. Metab. 81, 52-57. Hasegawa H., Sawabe K., Nakanishi N. and Wakasugi O. K. (2005) Delivery of exogenous tetrahydrobiopterin (BH4) to cells of target organs: Role of salvage pathway and uptake of its precursor in effective elevation of tissue BH4. Mol. Genet. Metab. 86, 2-10. Heales S. and Hyland K. (1989) Determination of quinonoid dihydrobiopterin by high-performance liquid chromatography and electrochemical detection. J. Chromatogr. B Biomed. Sci. Appl. 494, 77-85. Hebel R. and Stromberg M. W. (1976) Digestive system, in Anatomy of the Laboratory Rat, pp 48-51. The Williams & Wilkins Company. Hebel R. and Stromberg M. W. (1986) Digestive system, in Anatomy and Embryology of the Laboratory Rat, pp 50-54. BioMed Verlag. Hillcoat B. L. and Blakley R. L. (1966) Dihydrofolate reductase of Streptococcus faecalis. I. Purification and some properties of reductase from the wild strain and from strain A. J. Biol. Chem. 241, 2995-3001. Hillcoat B. L., Nixon P. F. and Blakley R. L. (1967) Effect of substrate decomposition on the spectrophotometric assay of dihydrofolate reductase. Anal. Biochem. 21, 178-189. Ho Y.-F., Lai M.-Y., Yu H.-Y., Huang D.-K., Hsueh W.-C., Tsai T.-H. and Lin C.-C. (2008) Application of rat in situ single-pass intestinal perfusion in the evaluation of pre-systemic extraction of indinavir under different perfusion rates. J. Formos. Med. Assoc. 107, 37-45. Holt P. R., Pascal R. R. and Kotler D. P. (1984) Effect of aging upon small intestinal structure in the Fischer rat. J Gerontol 39, 642-647. Howells D. W. and Hyland K. (1987) Direct analysis of tetrahydrobiopterin in cerebrospinal fluid by high-performance liquid chromatography with redox electrochemistry: prevention of autoxidation during storage and analysis. Clin. Chim. Acta 167, 23-30. Howells D. W., Smith I. and Hyland K. (1986) Estimation of tetrahydrobiopterin and other pterins in cerebrospinal fluid using reversed-phase high-performance liquid chromatography with electrochemical and fluorescence detection. J. Chromatogr. B Biomed. Sci. Appl. 381, 285-294. Hyland K. (1985) Estimation of tetrahydro, dihydro and fully oxidised pterins by high-performance liquid chromatography using sequential electrochemical and fluorometric detection. J. Chromatogr. B Biomed. Sci. Appl. 343, 35-41. Ichinose H., Katoh S., Sueoka T., Titani K., Fujita K. and Nagatsu T. (1991) Cloning and sequencing of cDNA encoding human sepiapterin reductase : An enzyme involved in tetrahydrobiopterin biosynthesis. Biochem. Biophys. Res. Commun. 179, 183-189. Jervis G. A. (1953) Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidizing system. Proc Soc Exp Biol Med 82, 514-515. Kapatos G. and Kaufman S. (1981) Peripherally administered reduced pterins do enter the brain. Science 212, 955-956. Katoh S., Arai Y., Taketani T. and Yamada S. (1974) Sepiapterin reductase in blood of various animals and of leukemic rats. Biochim. Biophys. Acta 370, 378-388. Kaufman B. T. (1974) Methotrexate-agarose in the purification of dihydrofolate reductase. Meth. Enzymol. 34, 272-281. Kaufman S. (1963) The structure of the phenylalanine-hydroxylation cofactor. Proc Natl Acad Sci U S A 50, 1085-1093. Kramer G., Zhang T., Kudlicki W. and Hardesty B. (1998) Preparation and application of chaperone-deficient Escherichia coli cell-free translation systems. Meth. Enzymol. 290, 18-26. Landmesser U., Dikalov S., Price S. R., McCann L., Fukai T., Holland S. M., Mitch W. E. and Harrison D. G. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111, 1201-1209. Leeson T. S., Leeson C. R. and Paparo A. A. (1985) The digestive system, in Testbook of Histology (5th, ed.), pp 365-375. Saunders International Edition, Philadelphia. Lu H.-H., Thomas J. D., Tukker J. J. and Fleisher D. (1992) Intestinal water and solute absorption studies:comparison of in situ perfusion with chronic isolated loops in rats. Pharm. Res. 9, 894-900. Lunte C. E. and Kissinger P. T. (1983) The determination of pterins in biological samples by liquid chromatography/electrochemistry. Anal. Biochem. 129, 377-386. Lynn R., Rueter M. E. and Guynn R. W. (1977) Mammalian brain dihydrofolate reductase. J. Neurochem. 29, 1147-1149. Ma C., Kudlicki W., Odom O. W., Kramer G. and Hardesty B. (1993) In vitro protein engineering using synthetic tRNAAla with different anticodons. Biochemistry 32, 7939-7945. Makulu D. R., Smith E. F. and Betino J. R. (1973) Lack of dihydrofolate reductase activity in brain tissue of mammalian species: possible implications. J. Neurochem. 21, 241-245. Mathews C. K., Scrimgeour K. G. and Huennekens F. M. (1965) Dihydrofolic reductase. Meth. Enzymol. 6, 364-368. Matsubara M., Katoh S., Akino M. and Kaufman S. (1966) Sepiapterin reductase. Biochim. Biophys. Acta 122, 202-212. McCrudden E. A. and Tett S. E. (1999) Improved high-performance liquid chromatography determination of methotrexate and its major metabolite in plasma using a poly(styrene-divinylbenzene) column. J. Chromatogr. B Biomed. Sci. Appl. 721, 87-92. McEvoy G. K., Snow E. K. and Kester L. (2006) Methotrexate, in AHFS Drug Information (McEvoy G. K., Snow E. K. and Kester L., eds), pp 1137-1144. American Society of Hospital Pharmacists, Bethesda, Maryland. McKellar M. (1949) The postnatal growth and mitotic activity of the liver of the albino rat. Am J Anat 85, 263-307. Moens A. L. M. D. and Kass D. A. M. D. (2007) Therapeutic potential of tetrahydrobiopterin for treating vascular and cardiac disease. J. Cardiovasc. Pharmacol. 50, 238-246. Nawa S. and Forrest H. S. (1962) Synthesis of the yellow pteridine, isosepiapterin. Nature 196, 169-170. Nichol C. A., Lee C. L., Edelstein M. P., Chao J. Y. and Duch D. S. (1983) Biosynthesis of tetrahydrobiopterin by de novo and salvage pathways in adrenal medulla extracts, mammalian cell cultures, and rat brain in vivo. Proc Natl Acad Sci U S A 80, 1546-1550. Powers A. G., Young J. H. and Clayton B. E. (1988) Estimation of tetrahydrobiopterin and other pterins in plasma by isocratic liquid chromatography with electrochemical and fluorimetric detection. J Chromatogr 432, 321-328. Prothero J. W. (1982) Organ scaling in mammals: The liver. Comp. Biochem. Physiol. A Physiol. 71, 567-577. Reinhard J. J. F., Chao J. Y., Smith G. K., Duch D. S. and Nichol C. A. (1984) A sensitive high-performance liquid chromatographic-fluoromotric assay for dihydrofolate reductase in adult rat brain, using 7,8-dihydrobiopterin as substrate. Anal. Biochem. 140, 548-552. Rezvani I. (2004) Defects in metabolism of amino acid, in Nelson Textbook of Pediatrics 17th Edition (Richard E. Behrman R. M. K., Hal B. Jenson, ed.), pp 397-402. Philadelphia. Savina P. M., Staubus A. E., Gaginella T. S. and Smith D. F. (1981) Optimal perfusion rate determined for in situ intestinal absorption studies in rats. J Pharm Sci 70, 239-243. Sawabe K., Wakasugi K. O. and Hasegawa H. (2004) Tetrahydrobiopterin uptake in supplemental administration: elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process. J. Pharmacol. Sci. 96, 124-133. Sawabe K., Suetake Y., Wakasugi K. O. and Hasegawa H. (2005a) Accumulated BH4 in mouse liver caused by administration of either 6R- or 6S-BH4 consisted solely of the 6R-diastereomer: Evidence of oxidation to BH2 and enzymic reduction. Mol. Genet. Metab. 86, 145-147. Sawabe K., Suetake Y., Nakanishi N., Wakasugi K. O. and Hasegawa H. (2005b) Cellular accumulation of tetrahydrobiopterin following its administration is mediated by two different processes; direct uptake and indirect uptake mediated by a methotrexate-sensitive process. Mol. Genet. Metab. 86, 133-138. Schnell J. R., Dyson H. J. and Wright P. E. (2004) Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct 33, 119-140. Shintaku H. (2002) Disorders of tetrahydrobiopterin metabolism and their treatment. Curr. Drug Metab. 3, 123-131. Smith G. K. (1987) On the role of sepiapterin reductase in the biosynthesis of tetrahydrobiopterin. Arch. Biochem. Biophys. 255, 254-266. Smith I., Clayton B. E. and Wolff O. H. (1975) New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet 1, 1108-1111. Spatzenegger M., Horsmans Y. and Verbeeck R. K. (2000) Differential activities of CYP1A isozymes in hepatic and intestinal microsomes of control and 3-methylcholanthrene-induced rats. Pharmacol. Toxicol. 86, 71-77. Tayeh M. A. and Marletta M. A. (1989) Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J. Biol. Chem. 264, 19654-19658. Thomas A. H., Lorente C., Capparelli A. L., Pokhrel M. R., Braun A. M. and Oliveros E. (2002) Fluorescence of pterin, 6-formylpterin, 6-carboxypterin and folic acid in aqueous solution: pH effects. Photochem. Photobiol. Sci. 1, 421-426. Thony B., Auerbach G. and Blau N. (2000) Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem. J. 347, 1-16. Widemann B. C., Balis F. M. and Adamson P. C. (1999) Dihydrofolate reductase enzyme inhibition assay for plasma methotrexate determination using a 96-well microplate reader. Clin. Chem. 45, 223-228. Woolf J. H., Nichol C. A. and Duch D. S. (1983) Determination of biopterin and other pterins in tissues and body fluids by high-performance liquid chromatography. J. Chromatogr. B Biomed. Sci. Appl. 274, 398-402. Young B., Lowe J. S., Stevens A. and Heath J. W. (2006) Wheater's Functional Histology : A Text and Colour Atlas, 5th Edition, pp 288-297. Churchill Livingstone. Yu H. Y., Lai Y. R., Kuo T. L. and Shen Y. Z. (1994) Effects of ethanol on pharmacokinetics and intestinal absorption of paraquat in animals. J Toxicol Sci 19, 67-75. Zorzi G., Redweik U., Trippe H., Penzien J. M., Thony B. and Blau N. (2002) Detection of sepiapterin in CSF of patients with sepiapterin reductase deficiency. Mol. Genet. Metab. 75, 174-177. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27150 | - |
| dc.description.abstract | Tetrahydrobiopterin（5,6,7,8-tetrahydropterin，BH4）為人體的內生性物質，具有多重重要功能，特別是在神經傳導物質catecholamines和 serotonin的生合成中，扮演著必要的調控因子。此外，BH4也是體內三種芳香性胺基酸水解酶phenylalanine hydroxylase、tyrosine hydroxylase和tryptophan hydroxylase的輔酶。
當體內缺乏 BH4，導致體內 neurotransmitters缺少時，會同時產生進行性的神經性症狀，稱為BH4 deficiency。此疾病和罕見疾病hyperphenylalaninemia（ICD-9-CM編號 270.1）有相關性。目前針對low phenylalanine 飲食控制成效不彰之新處置，為給予 BH4補充治療。 本研究運用in situ intestinal perfusion動物模式來進行，並使用體重約300∼350 g的成年Wistar大鼠。實驗設計分成以下四組：控制組是直接以生理食鹽水灌流小腸；BH4組則僅以含1 mg BH4/20 mL/300 g BW的灌流液進行灌流；MTX組為灌流生理食鹽水前 90 分鐘餵食 1 mg methotrexate（MTX）/100 g BW；MTX + BH4組是餵食MTX後再灌流BH4。於獲取小腸上皮細胞和肝臟均質化後，進一步測定其所內含有BH4、7,8-dihydrobiopterin（BH2）、sepiapterin含量及相關酵素dihydrofolate reductase （DHFR，EC 1.5.1.3）、sepiapterin reductase（SPR，EC 1.1.1.153）的活性。 結果發現：在肝臟與小腸上皮細胞中DHFR活性未觀察到MTX的抑制結果。而MTX會使肝臟與小腸上皮細胞中的SPR活性有明顯的增加，為控制組的120.9%∼167.7%。若灌流BH4，發現都不會影響肝臟與小腸上皮細胞DHFR及SPR活性。灌流 BH4會直接使肝臟內BH4含量提升，同時也造成 BH2 含量增加。藉由MTX餵食與灌流BH4，可發現MTX會抑制經由灌流BH4所產生的BH4含量增加現象，而使肝臟BH4含量與控制組相同。同時MTX也會減少肝臟內生性BH4含量。肝臟sepiapterin含量也不會因為MTX或BH4而有所變化。此外，小腸的BH4、BH2、sepiapterin含量都無法在實驗中被偵測出。 綜合上述結果，肝臟內BH4與BH2含量會因為BH4的給予而增加，MTX的給予而減少。在酵素活性上，MTX存在對肝臟與小腸SPR活性有明顯增加的影響。未來若能針對salvage生合成路徑進行詳細研究探討，並探討未成年大鼠此路徑和成年大鼠之間的異同點，便能夠對成年BH4 缺乏症病患的治療上有所貢獻。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-12T17:56:32Z (GMT). No. of bitstreams: 1 ntu-97-R94423007-1.pdf: 1299043 bytes, checksum: 8f449e260bb1cd5e47cd473fb8224da9 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 中文摘要……………………………………………………………………I
英文摘要…………………………………………………………..……...III圖目錄…………………………………………………………………..VIII表目錄………………………………………………………….…..….…..X英文縮寫名詞對照表……………………………………………...…....XII 1. 前言………………………………..…………………………........................……..1 2. 文獻探討………………………….………………………………………..............3 2.1 Tetrahydrobiopterin綜述…………………………….……………………………3 2.1.1 Tetrahydrobiopterin之物理與化學性質…………..….................…..……...3 2.1.2 Tetrahydrobiopterin生理功能............……………….……....……………...5 2.1.3 Tetrahydrobiopterin的生合成……………….………………………….…..6 2.1.4 Tetrahydrobiopterin研究綜述......................................................................10 2.2 Methotrexate簡介…...………………………….…................………………….13 2.2.1 Methotrexate物理與化學性質………….……………………...................13 2.2.2 Methotrexate藥品動態學………………………………………...……….13 2.2.3 Methotrexate藥理作用與臨床應用…………………………….....……...15 2.3 Dihydrofolate Reductase簡介…………….....….…………………....….………17 2.3.1 Dihydrofolate Reductase生化功能及相關文獻綜述…..........................…17 2.3.2 Dihydrofolate Reductase活性分析……….…………..........……..…….…19 2.4 Sepiapterin Reductase綜述………………...….………………..…......……..….24 2.5小腸生理學…………………………………..…...….…………………...……...27 2.6肝臟生理學…………………………...….…………………...………………….29 3. 研究目的………………………….………………………………………...........30 4. 實驗材料…………………………….……………………………………...........31 4.1 實驗動物…………………………………………….………………………….31 4.2 實驗藥品與試劑…………………………………….………………………….31 4.3 實驗儀器…………………………………………….………………………….33 5. 實驗步驟與方法…………………...……………………………………...........35 5.1 實驗動物處理………………....…………………….………………………….35 5.2 大鼠肝臟及小腸樣品製備…....……………………….……………………….38 5.2.1 肝臟樣品製備………………………………….…………………………38 5.2.2 小腸樣品製備………………………………….…………...…………….38 5.3 Tetrahydrobiopterin定量分析…...........……................……...………...……......41 5.4 Sepiapterin定量分析…...........……...……...……………………...……...…......44 5.5 Dihydrofolate Reductase酵素活性檢測…...……...……..………...………..…..46 5.6 Sepiaterin Reductase酵素活性檢測…...…………..……...………...…………..47 5.7蛋白質定量...……...………...………………………………………………...…48 5.7統計分析................................................................................................................49 6. 實驗結果…………………………….……………………...……………...…......51 6.1實驗動物基本資料……………....….…………………………………….…......51 6.2肝臟均質液及小腸上皮細胞蛋白質含量…….………........……………..…….53 6.3酵素活性檢測標準迴歸直線與確認………………..…………………………..54 6.4肝臟與小腸Dihydrofolate Reductase酵素活性之探討……........…........……..62 6.5肝臟與小腸Sepiapterin Reductase酵素活性之探討…………........…………..66 6.6肝臟Tetrahydrobiopterin及Dihydrobiopterin含量探討…........……................70 6.7肝臟內Sepiapterin含量探討…………………….................……………...……75 7. 討論………………………………………......……………………………............77 7.1實驗動物處理與肝臟、小腸樣品製備之相關討論………………………...…...77 7.2活性測定方法之討論…………………………….……………………..…....….78 7.3 HPLC測定方法之相關討論…………………………………………….....……80 7.4實驗結果討論………………………………………………….…….....…….….80 8. 結論與未來方向………………………...……………………...........………….88 9. 參考文獻………………………………….……………...........………………….90 | |
| dc.language.iso | zh-TW | |
| dc.subject | 四氫基喋呤 | zh_TW |
| dc.subject | tetrahydrobiopterin | en |
| dc.title | 大鼠肝臟中Tetrahydrobiopterin及相關酵素活性之探討 | zh_TW |
| dc.title | A Study on Tetrahydrobiopterin and Associated Enzyme Activities
in Rat Livers | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 余秀瑛,蔡東湖 | |
| dc.subject.keyword | 四氫基喋呤, | zh_TW |
| dc.subject.keyword | tetrahydrobiopterin, | en |
| dc.relation.page | 98 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-01-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-97-1.pdf 未授權公開取用 | 1.27 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。