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標題: 萘醌衍生物之核酸氧化損壞作用之研究
Oxidative DNA Damage Induce By Quinonoid Derivatives Of Naphthalene
作者: 康玉薇
wei, Kang yu
關鍵字: AP site;去鹼基核酸;Oxidative DNA damage;DNA SSB;氧化DNA損害;DNA單股斷鏈
出版社: 環境工程學系
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.
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