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Induction of Aldehydic DNA Lesions (ADL) by Chlorinated Catechols in Human MCF-7 Breast Cancer Cells
|關鍵字:||Aldehydic DNA Lesions (ADL);核酸醛基損害;Chlorinated Catechol;Oxidative DNA damage;Reactive Oxygen Species (ROS);含氯鄰位醌;類化合物;氧化DNA損害;活性氧化物||出版社:||環境工程學系||摘要:||
本研究在於探討不同的五氯酚(pentachlorophenol, PCP)醌類衍生物對人類乳腺癌細胞MCF-7，是否有能力導致細胞誘發核酸醛基損害(aldehydic DNA lesions, ADL)，並進而探討其作用機制。研究結果顯示，MCF-7細胞內經由預先添加降低細胞內的榖胱甘肽glutathione (GSH)之藥劑，N-ethylmaleimide (NEM)，再與tetrachlorocatechol (Cl4CAT) (500 μM)反應18小時後，能提高誘發MCF-7細胞生成ADL 的能力(p<0.05)。不同含氯數之PCP醌類衍生物其誘發生成ADL的能力如下：Cl4CAT > 4,5-dichlorocatechol (4,5-Cl2CAT) ≈ 3,4,5-trichlorocatechol (3,4,5-Cl3CAT) ≈ 4-chlorocatechol (4-ClCAT)，這個實驗結果不同於在小牛胸腺DNA中不同含氯數之PCP醌類衍生物誘發生成ADL之結果。此外，預先處理Fe(II)螯合劑dipyridyl (DPD)及Cu(I)螯合劑2,9-Dimethyl-1,10-phenanthroline hydrochloride (DPH)能降低Cl4CAT在細胞內誘發生成ADL的能力，這個結果亦顯示，Cu(I)螯合劑DPH及Fe(II)螯合劑DPD有抑制細胞誘發生成ADL的能力。進一步實驗結果顯示，過氧化氫(hydrogen peroxide)為MCF-7細胞誘發生成ADL其過程中參與之主要ROS物種之一。同時，MCF-7細胞內由Cl4CAT所誘發之ADL約有70 %可被putrescine移除。此一研究證據證明，Cl4CAT在MCF-7細胞中主要經由氧化壓力誘發生成ADL。總結本研究之結果證實在人類乳癌細胞MCF-7中Cl4CAT可經由氧化還原循環過程中誘發ROS，並進一步生成ADL，此外不同含氯數之chlorocatechols對於DNA所造成之損害有明顯之差異現象。
The primary purpose of this research is to examine the potentials of the induction aldehydic DNA lesions (ADL) by various catechol derivatives of pentachlorophenol (PCP) in human MCF-7 breast cancer cell line. Results from the analyses of ADL indicated that when cells pretreated with the glutathione -depleting agent, N-ethylmaleimide (NEM), increases in the number of ADL was detected in MCF-7 cells exposed to tetrachlorocatechol (Cl4CAT) (500 μM) (p<0.05). The DNA lesions induced by various degree of chlorination of PCP-derived catechols decrease in the rank order Cl4CAT > 4,5-dichlorocatechol (4,5-Cl2CAT) ≈ 3,4,5-trichlorocatechol (3,4,5-Cl3CAT) ≈ 4-chlorocatechol (4-ClCAT). This results was at odds with the theme that dechlorination potentiates the induction of ADL in calf thymus DNA exposed to various degree of chlorination of PCP-derived catechols. Additionally, pretreatment with dipyridyl, an iron (II)-specific chelator, significantly reduced the formation of ADL in cells exposed to Cl4CAT. Similar observation was also detected in cells pretreated with 2,9-Dimethyl-1,10-phenanthroline hydrochloride (DPH), an copper (I)-specific chelator, where DPH significantly inhibited the formation of ADL in cells exposed to Cl4CAT. Further investigation indicated that hydrogen peroxide participate in the induction of ADL by Cl4CAT in MCF-7 cells. The data also indicated that the ADL induced by Cl4CAT contain ~70 % putrescine-excisable ADL in MCF-7 cells. Overall, this evidence confirmed that the ADL induced by Cl4CAT in MCF-7 cells are derived from oxidative events. In summary, these data demonstrate that similar to its para-isomer, Cl4CAT may induce significant oxidative modifications in human breast cancer cells and that differences in the degree of chlorination modulate the DNA-damaging potentials of various chlorocatechol derivatives.
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