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研究生(外文):Hui-Ju Wu
論文名稱(外文):Interactions of Areca Quid and Cigarette Smoke Components Assessed by Comet Assay In Vitro and In Vivo
指導教授(外文):Tsung-Yun Liu
外文關鍵詞:areca quid
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根據台灣地區流行病學報告指出,嚼食檳榔與吸菸對口腔癌的發生有加成性的影響。本研究即利用彗星分析法探討檳榔與香菸中成份的交互作用。台灣檳榔塊主要是由檳榔、荖花及石灰所組成。荖花中含有一酚類化合物hydroxychavicol (HC),被認為會對細胞DNA造成氧化性傷害。香菸中含有多種有毒物質,如尼古丁、benzo[a]pyrene (B[a]P) 及4-(methylnitrosamino)- 1-
(3-pyridyl)-1-butanone (NNK) 等。本論文研究結果發現HC (10 mM) 和 B[a]P (1 mM) 同時給予時,對口腔癌細胞株OEC-M1 造成的DNA傷害會比單獨使用HC或B[a]P時顯著增加。進一步利用Endonuclease III 和 formamidopyrimidine glycosylase兩種酵素處理,發現DNA的斷裂會增加,說明HC及B[a]P誘發的DNA傷害部分來自於氧化性的DNA鍵結物。此外,嚼食檳榔時石灰會使口腔環境變成鹼性 (pH > 10),而此鹼性化的環境也可能參與檳榔與香菸的交互作用。尼古丁為香菸中的生物鹼,其穿透細胞膜的能力隨酸鹼值的增加而提高。因此,本論文利用觀察尼古丁在不同酸鹼環境下 (pH 6.5與8.0) 對DNA的傷害,藉此探討酸鹼環境對尼古丁毒性的影響。此外,也會對香菸濃縮物進行測試。結果顯示,在鹼性環境下 (pH 8.0),尼古丁與香菸濃縮物對DNA的傷害明顯較在酸性環境下 (pH 6.5) 來的大。當細胞預先處理N-acetyl-cysteine或catalase能降低尼古丁產生的DNA傷害,顯示尼古丁誘發的DNA傷害可能與氧化性壓力有關。進一步以流式細胞儀分析發現尼古丁會造成細胞內8-hydroxyguanine的增加,更證實了尼古丁會造成氧化性傷害的可能性。最後,則利用倉鼠的口腔頰囊來探討酸鹼環境對NNK毒性的影響。發現NNK在鹼性環境下 (pH 8.7) 對倉鼠口腔頰囊之keratinocytes造成的DNA傷害會較在正常酸鹼值下(pH 7.0) 來的高。綜合來說,目前的研究結果指出HC和B[a]P會對DNA的傷害有加成性的影響;另外,在鹼性環境下,香菸中的毒害物質對DNA的傷害會增加,代表著鹼性環境在提高香菸毒性中扮演一重要角色。
Epidemiological studies indicated that chewing areca quid (AQ) and smoking have synergetic potential in developing oral cancer in Taiwan. This study was designed to test their interaction by Comet assay. The composition of AQ used in Taiwan includes areca nut, Piper betle inflorescence and lime. Hydroxychavicol (HC) is a phenolic compound contained in Piper betle inflorescence, and it can cause oxidative DNA damage. Cigarette smoke (CS) contains various toxic chemicals, such as nicotine, benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) etc. The results indicated that combination of HC (10 mM) and B[a]P (1□mM) in OEC-M1 cells caused a significant increase of DNA damage compared with HC or B[a]P alone as evidenced by comet movement. Endonuclease III and formamidopyrimidine glycosylase digestion increased DNA strand breaks, implying that part of DNA damage induced by HC or B[a]P came from excision of oxidative DNA adducts. In addition, the alkalization of saliva (pH > 10) caused by lime might also contribute to the interaction with cigarette components. Nicotine, a cigarette-containing alkaloid, penetrates biomembrane more efficiently with increasing pH. The DNA damage potential of nicotine and cigarette smoke condensate (CSC) was tested at different pH (6.5 and 8.0). Nicotine (10□ mM) and CSC (20 mg/ml) induced significantly more DNA damage at pH 8.0 than at pH 6.5. When cells were pretreated with N-acetyl-cysteine or catalase, a reduction in DNA damage was observed; demonstrating that nicotine induced DNA damage might be mediated by oxidative stress. Furthermore, nicotine caused the increase of 8-hydroxyguanine levels as shown by flow cytometry. Finally, hamster cheek pouch was used to investigate the pH effect on NNK toxicity. Under the alkaline condition (pH 8.7), NNK caused higher DNA damage of the hamster cheek pouch keratinocytes than that in normal pH (pH 7.0). Overall, these findings indicated that there is additive effect on DNA damage caused by HC and B[a]P, and under alkaline condition, DNA damage caused by cigarette containing toxic chemicals was increased, meaning that the alkaline condition might be an important factor to enhance the toxicity of CS.
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