臺灣博碩士論文加值系統

本研究目的在於探討萘醌之鄰位醌類代謝物（ortho-quinonoid）經由氧化還原循環生成活性氧化物（reactive oxygen species, ROS）之潛力，進而對核酸產生氧化破壞作用，包括去鹼基核酸（AP sites）及DNA單股斷鏈（DNA SSB）之作用機制。研究結果顯示，萘之鄰位醌類活性代謝物，包括1,2-naphthoquinone (1,2-NQ)及1,2-dihydroxynaphthalene (1,2-NCAT)，於活體外與小牛胸腺DNA（ctDNA）反應，皆可在過渡性金屬Cu(II)（20 μM）及NADPH（100 μM）的存在下，誘發ctDNA之DNA SSB及AP sites同步生成。經由添加ROS移除劑及抗氧化劑之結果顯示，1,2-NQ在Cu(II)及NADPH存在下，可經由氧化還原循環生成ROS而誘發AP site之核酸損害作用，其主要之ROS物種為H2O2，•OH則可能提供部分作用。由於Cu(I)-specific螯合劑能抑制Cu(II)與1,2-NQ誘發的AP sites之生成，此一結果顯示Cu(II)/Cu(I)間的氧化還原循環作用在此反應扮演重要角色，同時Cu(I)與ROS中之H2O2所結合之過氧化物－Cu(I)OOH，可能為實際參與誘發DNA SSB及AP sites生成之物種。此外，生物體內小分子物質glutathione (GSH)，可抑制Cu(II)與1,2-NQ所誘發的AP sites之生成，顯示GSH可能是與1,2-NQ結合後中斷其氧化還原之循環，終止ROS生成進而抑制DNA之氧化損壞作用。此外，GSH亦有可能是直接與ROS反應，移除ROS達到保護DNA之作用。相對於ROS所誘發之AP sites，1,2-NQ則需高濃度（5 mM）時與核酸形成DNA adduct，再進行去嘌呤作用才能生成AP sites。此外，1,2-NQ經由氧化還原循環產生ROS而誘發之AP sites種類，經確認約70%為putrescine可切除之AP sites。總結本研究之結果證實，萘之鄰位醌類代謝物可經由誘發ROS進而導致核酸之五碳醣之氫原子移除作用（hydrogen abstraction），造成同步生成DNA SSB及AP sites之核酸損壞。

Oxidative DNA damage induced by quinoid metabolites of naphthalene, e.g., 1,2-naphthoquinone (1,2-NQ), 1,2-dihydroxynaphthalene (1,2-NCAT), was investigated in calf thymus DNA (ctDNA). Results indicated that in the presence of Cu(II) and NADPH, parallel increases in DNA strand breaks and abasic (AP) sites was detected in calf thymus DNA exposed to 1,2-NQ and 1,2-NCAT over the corresponding control. Further investigation indicated that the DNA damage induced by 1,2-NQ plus Cu(II) and NADPH was inhibited by the additions of catalase, copper(I)-specific chelator, hydroxyl radical scavenger and glutathione whereas superoxide dismutase did not prevent the induction of AP sites. These results suggest the involvement of Cu(I)、hydrogen peroxide and hydroxyl radical in the induction of oxidative DNA damage by 1,2-NQ. At high concentration ( 5 mM ), naphthalene quinoid alone may induce AP sites via epurination/ depyrimidination naphthalene quinone-DNA adducts. In contrast, of induced AP sites in.Further characterization of the AP sites confirmed that 1,2-NQ induced predominantly（70％）putrescine-excisable AP sites in ctDNA. In summary, quinononid derivatives of naphthalene may induce significant oxidative modifications in ctDNA via hydrogen abstract atome from deoxyribose, resulting in the parallel formation of AP sites and strand breaks.

中 文 摘 要 I
Abstract III
縮 寫 表 IV
目 錄 ……………………………………………………………………………………. V
圖 目 錄 VII
第一章 前 言 1
1-1 研究緣起 1
1-2 研究目的 1
第二章 文獻回顧 3
2-1 多環芳香族碳氫化合物（PAHs） 3
2-1-1 PAHs之簡介 3
2-1-2 PAHs醌類化物之致基因毒害作用與活性氧化物（ROS）之生成 3
2-2 萘之代謝途徑及致基因毒害作用 6
2-2-1萘（naphthalene）之物化特性及健康危害 6
2-2-2萘之代謝途徑 7
2-2-3萘醌類化合物之致基因毒害作用 9
2-3 氧化所引起之DNA損害作用（oxidative DNA damage） 10
2-3-1 活性氧化物（reactive oxygen species, ROS） 10
2-3-2 氧化壓力誘發之DNA損害（DNA damage resulting from oxidative stress） 11
2-3-3 生物體之抗氧化防禦系統 12
2-3-4 氧化壓力與疾病之相關性 13
2-4 DNA損害修補 14
2-4-1 DNA損害之修補機制 14
2-4-2去鹼基核酸 18
2-5去鹼基核酸之偵測 19
第三章 實驗材料與方法 23
3-1 實驗材料 23
3-1-1 水 23
3-1-2 化學藥品 23
3-1-3 去鹼基核酸分析藥品 23
3-1-4 電泳分析藥品 24
3-1-5 實驗設備 24
3-2 實驗方法 24
3-2-1 鄰位萘醌誘發DNA氧化損壞作用之能力 24
3-2-2 萘醌誘發DNA氧化損壞作用之機制 25
3-2-3 萘醌誘發核酸生成3’-及5’-cleaved AP sites之結構確認 27
3-3分析方法 27
3-4 數據分析 32
第四章 實驗結果 33
4-1萘醌誘發DNA氧化損害作用之能力 33
4-1-1 1,2-萘醌（1,2-NQ）誘發DNA AP sites與DNA SSB之生成 33
4-1-2過渡性金屬離子與NADPH之影響 36
4-1-3 1,2-dihydroxynaphthalene（1,2-NCAT）誘發DNA AP sites之生成 38
4-1-4 NADPH及銅之存在對1,2-NQ及1,2-NCAT誘發DNA AP sites之影響 39
4-2萘醌誘發DNA氧化損壞作用之機制 41
4-2-1 ROS移除劑之影響 41
4-2-2抗氧化劑之影響 44
4-2-3 Cu(I) 螯合劑（bathocuproinedisulfonic acid, BAT）之影響 44
4-2-4 還原態麩胱甘胺（glutathione, GSH）及cysteine之影響 46
4-3萘醌誘發DNA生成3’ 端或5’ 端斷裂之AP sites （3’-及5’-cleaved AP sites）之結構確認 49
第五章 討 論 51
第六章 結論與建議 56
6-1 結論 56
6-2未來研究方向及建議 57
參考文獻 59

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