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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉秉惠(Biing-Hui Liu) | |
dc.contributor.author | Yen-Hua Pien | en |
dc.contributor.author | 卞彥驊 | zh_TW |
dc.date.accessioned | 2021-06-17T02:46:06Z | - |
dc.date.available | 2025-08-17 | |
dc.date.copyright | 2020-09-01 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-17 | |
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Y., Development and validation of liquid chromatography-tandem mass spectrometry method for quantification of plasma metanephrines for differential diagnosis of adrenal incidentaloma. Annals of Laboratory Medicine, 2015. 35(5): p. 519-522. 32. Eisenhofer, G., Peitzsch, M., Kaden, D., Langton, K., Mangelis, A., Pamporaki, C., Masjkur, J., Geroula, A., Kurlbaum, M., Deutschbein, T., Beuschlein, F., Prejbisz, A., Bornstein, S. R., and Lenders, J., Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine. Clinica Chimica Acta, 2019. 490: p. 46-54. 33. Mullins, F., O'Shea, P., FitzGerald, R., and Tormey, W., Enzyme-linked immunoassay for plasma-free metanephrines in the biochemical diagnosis of phaeochromocytoma in adults is not ideal. Clinical Chemistry and Laboratory Medicine, 2011. 50: p. 105-10. 34. Weismann, D., Peitzsch, M., Raida, A., Prejbisz, A., Gosk, M., Riester, A., Willenberg, H. S., Klemm, R., Manz, G., Deutschbein, T., Kroiss, M., Darr, R., Bidlingmaier, M., Januszewicz, A., Eisenhofer, G., and Fassnacht, M., Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma. European Journal of Endocrinology, 2015. 172(3): p. 251-260. 35. Xiao, J.F., Zhou, B., and Ressom, H. W., Metabolite identification and quantitation in LC-MS/MS-based metabolomics. Trends in Analytical Chemistry, 2012. 32: p. 1-14. 36. Stroobant, E.d.H.V., Ch.6 Analytical information. Mass Spectrometry: Principles and Applications, 2007. 3rd edition: p. 247. 37. Petteys, B.J., Graham, K. S., Parnas, M. L., Holt, C., and Frank, E. L., Performance characteristics of an LC-MS/MS method for the determination of plasma metanephrines. Clinica Chimica Acta, 2012. 413(19-20): p. 1459-1465. 38. Mendes, V.M., Coelho, M., Tome, A. 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C., Lunggren, Osten, Mellström, Dan, Patrick, Alan L., Stefanick, Marcia L., Nakamura, Kozo, Yoshimura, Noriko, Zmuda, Joseph, Vandenput, Liesbeth and C. Ohlsson, Osteoporotic Fractures in Men Research, Group, Evidence for geographical and racial variation in serum sex steroid levels in older men. The Journal of clinical endocrinology and metabolism, 2010. 95(10): p. E151-E160. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68994 | - |
dc.description.abstract | 嗜鉻細胞癌(pheochromocytomas)為一種罕見的嗜鉻細胞腫瘤,其主要症狀為分泌過多兒茶酚胺(catecholamine)導致之高血壓和心搏過速,若沒有及時診斷治療可能致命。患者經常因為其臨床表現和許多內分泌疾病類似而延後就醫,目前以偵測兒茶酚胺之甲基化代謝物:變腎上腺素(metanephrine, MN)和去甲基變腎上腺素(normetanephrine, NMN)做為嗜鉻細胞瘤的重要標的物,然而變腎上腺素和去甲基變腎上腺素在正常人和發病初期血漿含量極低,因此建立一套高靈敏的檢測方法做為嗜鉻細胞瘤的診斷十分重要。本篇研究使用少量血漿樣品以弱鹼型離子交換管柱進行固相萃取去除多餘蛋白質,再以液相層析串聯質譜儀進行定性及定量分析,並將進一步確認此方法之線性、偵測極限、準確性、回收率及基質效應。除此之外,本研究利用人類肝細胞成分模擬體內代謝反應,以三段式四極桿柱和高解析液相層析質譜儀鑑定其二次代謝產物,並在真實檢體中檢驗此代謝物,判斷其做為嗜鉻細胞瘤之標記物的可能性。結果顯示此方法表現出良好的準確性和穩定性,在病人檢體中亦能檢出;經體外培養合成的變腎上腺素和去甲基變腎上腺素之硫酸化產物,分別為metanephrine-sulfate (MN-S) 和normetanephrine (NMN-S )也藉由液相層析質譜儀鑑出,確認精確質量以驗證其結構,MN-S的訊號值在正常人體(n=11)和確診病患(n=6)體內之p值小於0.05,未來可應用於嗜鉻細胞瘤之診斷。 | zh_TW |
dc.description.abstract | Pheochromocytomas are rare chromaffin cell tumors. The development of the disease commonly induces hypertension and tachycardia by producing excess catecholamines, which shows similar symptoms to endocrine diseases. This makes it hard to be diagnosed at early stage. In addition, previous studies indicated that it is associated with specific germline mutation. In clinical diagnosis, the methylated metabolites of catecholamines, metanephrine (MN) and normetanephrine (NMN) are used as specific biomarkers for diagnosis of pheochromocytomas. However, MN and NMN in plasma are at trace level both in healthy people or in patients with early-stage illness. In this study, we aim at establishing a highly sensitive assay to determine MN and NMN in human plasma. The samples were extracted and analyzed using weak cation exchange solid phase extraction couple to liquid chromatography mass spectrometry (LC-MS). The method is validated for linearity, limit of quantitation, recovery and matrix effect. Besides, we synthesized the phase II metabolites of MN and NMN in vitro with human liver microsomes and cytosols and determined the sulfo-metabolites, MN-S from MN and NMN-S from NMN, using LC-MS/MS and liquid chromatography-high resolution mass spectrometry (LC-HRMS) to confirm the formulas by their fragment pattern and accurate mass. The sulfate-conjugated metabolites were detected in 17 human plasma specimens (11 normal people and 6 patients) and showed significant positive correlation with their parent substances (p<0.001). MN-S showed significant difference between the normal and patients group (p<0.05) The sulfation metabolites may be potential biomarker for pheochromocytomas. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T02:46:06Z (GMT). No. of bitstreams: 1 U0001-1708202001020600.pdf: 6062749 bytes, checksum: 101f855859674d2b5d800af68e43dfe2 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 謝誌 ii 中文摘要 iii Abstract iv Contents vi Figures viii Tables x Terminology xi Chapter 1 Introduction 1 1.1 Background 1 1.2 Metabolism of MN and NMN 4 1.3 Phase II metabolism 6 1.4 Mass spectrometry and metabolite identification 7 1.5 Establish the MRM transitions for metabolites 9 1.6 Objectives and aims 9 Chapter 2 Material and Methods 12 2.1 Material 12 2.2 Instrument 14 2.2.1 Liquid chromatography-mass spectrometry (LC-MS) 14 Triple QuadTM 5500 14 Triple Quad 3000 15 2.2.2 Liquid chromatography-high resolution mass spectrometry (LC-HRMS) 17 2.3 Method 17 2.3.1 Sample collection and preparation 17 Solid Phase Extraction 18 Protein Precipitating for MN and NMN 18 Protein Precipitating for Metabolites of MN and NMN 19 2.3.2 Establishment of MRM transitions 19 2.3.3 Method validation 20 Linearity 20 Matrix effect 20 Intra- and inter-day precision 21 Recovery 21 2.3.4 Phase II sulfation conjugation 22 2.3.5 Phase II glucuronidation conjugation 23 2.3.6 Statistical analysis 23 3.1 Validation of MN and NMN determination 25 Linearity 34 Matrix effect 37 Intra- and inter-day precision 38 Recovery 38 3.2 Identification of phase II metabolites in vitro of MN and NMN 40 3.2.1 Phase II metabolite in vitro of MN 40 3.2.2 Phase II metabolite in vitro of NMN 46 3.3 Identification of MN and NMN in vivo 55 3.4 Identification of MN-S and NMN-S in vivo 58 Chapter 4. Conclusion 67 Reference 68 Supplementary 73 | |
dc.language.iso | en | |
dc.title | 利用液相層析質譜儀檢測人類血液之變腎上腺素、去甲變腎上腺素和其二次代謝物 | zh_TW |
dc.title | Determination of Metanephrine, Normetanephrine and Phase II Metabolites in Human Plasma Using LC-MS | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 碩士 | |
dc.contributor.author-orcid | 0000-0003-0499-2214 | |
dc.contributor.advisor-orcid | 劉秉惠(0000-0002-8662-0512) | |
dc.contributor.coadvisor | 陳珮珊(Pai-Shan Chen) | |
dc.contributor.coadvisor-orcid | 陳珮珊(0000-0002-2047-4276) | |
dc.contributor.oralexamcommittee | 陳沛隆(Pei-Lung Chen),吳婉禎(Wan-Chen WU),蔡宗能(Tsung-Neng Tsai) | |
dc.contributor.oralexamcommittee-orcid | 陳沛隆(0000-0002-5640-3074),吳婉禎(0000-0002-2731-5331) | |
dc.subject.keyword | 嗜鉻細胞瘤,變腎上腺素,去甲基變腎上腺素,液相層析串聯質譜,高解析質譜,體外肝細胞,二級代謝物鑑定, | zh_TW |
dc.subject.keyword | pheochromocytomas,metanephrine,normetanephrine,liquid chromatography tandem mass spectrometry,liquid chromatography-high resolution mass spectrometry,metabolite identification, | en |
dc.relation.page | 134 | |
dc.identifier.doi | 10.6342/NTU202003647 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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