Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/5221
標題: 發展一修正型MT分析法來探討萘醌類衍生物之蛋白質胼合物
Development of a modified MT assay to analyze the protein adducts of quinonoid derivatives naphthalene
作者: 王姿文
Wang, Tzu-Wen
關鍵字: 萘蛋白質胼合物
Naphthalene
白蛋白胼合物
生物指標
Protein adduct
Biomarker
PAH
1,2-Naphthoquinone
1,4-Naphthoquinone
Albumin adduct
出版社: 環境工程學系所
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摘要: 本研究係利用生物性指標分析方法,針對萘醌類化物與蛋白質所形成之共價鍵結產物-蛋白質胼合物 (protein adduct),作為推估萘醌類化物於標的器官之組織劑量。本研究建立一修正型MT衍生方法 (modified MT assay),以TFAA(Trifluoroacetic acid anhydride)作為衍生劑,在強酸環境下催化,將萘醌類化物與蛋白質上的cysteine之硫原子鍵結之胼合物自結構中移除,並經由溶劑萃取濃縮,利用氣相層析電子撞擊離子源與負離子化學性離子化質譜儀(GC/EI/MS及GC/NICI/MS),進行定性與定量分析,同時也建立運用高效能液相層析儀純化萘醌類化物之cysteine胼合物,作為定量所需檢量線之標準品。同時利用同位素內標準品,完成對萘醌類化物與cysteine及蛋白質形成之胼合物之分析方法最佳化之測試,推估修正型MT分析方法之偵測極限在此研究中約為1 pmole。並針對小牛血清白蛋白、美國Sigma-Aldrich公司所購買人類血清白蛋白,及台灣地區一般人類血清提純白蛋白之背景値分析。結果發現,在小牛血清白蛋白並無偵測到1,2-NPQ及1,4-NPQ之蛋白質胼合物。美國Sigma-Aldrich公司所購買人類血清白蛋白1,2-NPQ及1,4-NPQ之蛋白質胼合物其背景値範圍約82.8及101 pmole/g protein。台灣地區方面某捐血中心之血液樣本中,男性(n=8)及女性(n=8)的1,2-NPQ及1,4-NPQ之蛋白質胼合物背景値範圍介於18.4 to 1142 pmole/g of protein,且女性背景値略高於男性。最後,本研究中亦針對1,2-NPQ與1,4-NPQ於活體外與胎牛血清白蛋白、人類血清白蛋白及人類血清反應之一次移除速率常數(First-Order Elimination Rate constants)Ke進行探討,推估其値約略介於1.92-40.6(hr-1)。
The objective of this research is to develop a biochemical assay using protein adducts as biomarker of exposure to assess the cumulative body burden of naphthoquinones in human serum. Naphthalene a congeneric from of PAHs, is an important industrial chemical and is formed as a byproduct of combustion. Both 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are reactive metabolites of naphthalene that are though to be responsible for the naphthalene-induced cytotoxicity and genotoxicity. In this work, we developed a modified MT assays using trifluoroacetic anhydride (TFAA) and methanesulfonic acid (MSA) as catalysts to cleave cysteinyl adducts of naphthoquinones on proteins. A modified MT assays is presented to simultaneously measure cysteinyl adducts of major naphthalene metabolites, 1,2-NPQ and 1,4-NPQ in albumin. The cleaved adducts are recovered by organic solvent extraction and analyzed by gas chromatography / mass spectrometer (GC-MS). Additionally, the synthetic cysteinyl adduct of 1,2-NPQ and 1,4-NPQ was further purified by HPLC-UV and was used as standards to quantify modified proteins. The limit of detection of this modified MT assay is estimated to be ~1 pmole. The optimized MT assay was used to estimate the background levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on albumin, including bovine serum albumin (Sigma-Aldrich Inc.), human serum albumin (Sigma-Aldrich Inc.), and human serum albumin derived from unexposed blood donors in Taiwan. We did not detected any background level of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ in bovine serum albumin purchased from Sigma. In contrast, the background levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on human serum albumin obtained from Sigma were estimated to be 82.8 and 101 pmole/g, respectively. Additionally, we detected the background levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on human serum albumin derived from blood donors in Taiwan ranging from 18.4 to 1142 pmole/g of protein. On the average, the background levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on human serum albumin of male donor are lower than those of female. Finally, preliminary results from the reaction rate constant analyses indicated that the overall rate constants of elimination of naphthoquinones, including 1,2-NPQ and 1,4-NPQ, in human serum were estimated to be between 1.92-40.6(hr-1).
URI: http://hdl.handle.net/11455/5221
其他識別: U0005-2807200611412900
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2807200611412900
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