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研究生:吳舒璿
研究生(外文):Shu-Hsuan
論文名稱:β-Apo-8’-胡蘿蔔素單獨或合併Benzo[a]pyrene誘發A549細胞傷害及CytochromeP4501A2表現與Quercetin的抑制效應
論文名稱(外文):β-Apo-8’-carotenal alone or combined with benzo[a]pyrene induces cell damage and cytochrome P4501A2 in A549 cells and the inhibiting effects of quercetin
指導教授:葉姝蘭
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:營養學研究所
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:69
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雖然許多流行病學調查結果顯示,攝取富含β-胡蘿蔔素之深色蔬菜水果可以減少心臟血管疾病與多種癌症的發生,但人體試驗結果卻發現補充β-胡蘿蔔素,可以增加抽菸者肺癌的發生。β-胡蘿蔔素對香菸所造成的傷害作用具增強效果,其作用被認為可能來自於高劑量及其氧化產物的影響。由於類黃酮是蔬菜水果中富含的另一天然抗氧化成分,因此可能也有助於蔬菜水果對健康的益處。但β-胡蘿蔔素氧化產物以及類黃酮對β-胡蘿蔔素的影響之研究並不多見。因此,利用人類肺癌株化細胞A549為細胞模式,我們進行以下研究:第一部份先探討不同劑量β-胡蘿蔔素及其氧化產物β-apo-8’-carotenal單獨及與香菸中致癌成分benzo[a]pyrene (BaP)共同作用時,對細胞DNA斷裂、脂質過氧化及cytochrome P450 (CYP)1A2蛋白表現的影響。A549細胞先以2, 5或20 μM β-胡蘿蔔素及β-apo-8’-carotenal 培養1小時,接著再加入20 μM BaP培養24小時,利用comet assay來分析DNA斷裂的程度,並利用Thiobarbituric acid試劑分析脂質過氧化,並利用西方墨點法測定CYP1A2的表現。結果發現,β-apo-8’-carotenal單獨就會誘發DNA傷害,並具劑量關係;其濃度達2 μM 時即較控制組顯著增加(P < 0.05),但β-胡蘿蔔素本身即使到達20 μM亦無顯著影響。另外,20 μM β-apo-8’-carotenal亦顯著增加細胞脂質過氧化程度,β-胡蘿蔔素本身則否。在BaP共同作用下,β-apo-8’-carotenal會增加細胞DNA斷裂,並具劑量關係,但2及5 μM β-胡蘿蔔素則具輕微抑制效果。雖然20 μM b-apo-8’-carotenal及β-胡蘿蔔素均增強BaP誘發的 CYP1A2蛋白表現,但b-胡蘿蔔素本身對CYP1A2量沒有影響,反之 β-apo-8’-carotenal單獨即有誘發效果。另外,我們也發現,CYP酵素抑制劑1-aminobenzotriazole (ABT)能夠抑制BaP或AC所誘發的DNA傷害,顯示CYP酵素活化會增加DNA傷害。
為瞭解類黃酮的影響情形,第二部分研究則選用四種容易從蔬菜水果中獲得的類黃酮,quercetin、naringin、rutin及naringenin進行測試。由於quercetin抑制A549細胞CYP1A2的表現及BaP誘發的DNA傷害效果最好,抑制率分別達30.6 %及39.7 %,因此進一步將A549細胞和quercetin與β-apo-8’-carotenal或β-胡蘿蔔素共同培養,測試quercetin的影響,結果顯示,quercetin能抑制β-apo-8’-carotenal單獨或兩種類胡蘿蔔素分別合併BaP所誘發的DNA斷裂,也可抑制β-apo-8’-carotenal單獨或β-胡蘿蔔素合併BaP所誘發的CYP1A2蛋白表現。
以上結果證實β-胡蘿蔔素的氧化產物之一,β-apo-8’-carotenal會對DNA 造成傷害,並增加CYP1A2表現,β-胡蘿蔔素則否;與BaP共同作用下,低劑量β-胡蘿蔔素具輕微抑制傷害效果,β-apo-8’-carotenal則否。此外,quercetin可抑制β-apo-8’-carotenal所誘發的傷害,而可增加β-胡蘿蔔素的安全性。
Epidemiological studies have shown inverse relationship between the intake of fruits and vegetables, which are rich in β-carotene, and the risk of cancers especially in smokers. Contradictorily, clinical trials showed that β-carotene supplementation may be harmful to smokers. The high doses and the oxidative products of β-carotene have been considered to contribute to the harmful effects. Since flavonids are another group of natural antioxidants ubiquitously existing in fruits and vegetablews, they possibly contribute to the well effects of fruits and vegetables. However, little work on the oxidative products of β-carotene and the effects of flavonids on the behavior of β-carotene has been done. In the present study, we used cell model to investigate: First, the individual and combined effects of β-carotene, β-apo-8’-carotenal (an oxidative product of β-carotene), and benzo[a]pyrene (BaP) on DNA damage, lipid peroxidation and the expression of cytochrome P450 (CYP) 1A2 in A549 cells. A549 cells were first pre-incubated with 2, 5 or 20 μM β-carotene or β-apo-8’-carotenal for 1 hr, followed by incubation with 20 μM BaP for 24 hrs. DNA damage was measured by comet assay, and lipid peroxidation was measured as thiobarbituric acid reactive substances. Expression of CYP1A2 was determined using western blotting. The results showed that β-apo-8’-carotenal alone significantly, and in a dose dependent manner, increased DNA damage and the expression of CYP1A2, whereas β-carotene itself even at 20 μM had no effects. β-apo-8’-carotenal at 20 μM significantly increased the level of lipid peroxidation. β-apo-8’-carotenal enhanced DNA damage and CYP1A2 expression induced by BaP in a dose-dependent manner, whereas β-carotene at 2 and 5 μM slightly suppressed the damage to DNA. In addition, ABT, a non-specific CYP inhibitor, partly blocked the effects on DNA damage induced by β-apo-8’-carotenal alone as well as β-apo-8’-carotenal or β-carotene combined with BaP.
Second, using certain common flavonids, quercetin, naringin, rutin and naringenin, we examined whether flavonids suppress the CYP1A2 protein levels and the DNA break in A549 cells with or without exposure to BaP. Since quercetin had the best ability in both, we added quercetin to further incubation experiments. The results demonstrated that quercetin significantly inhibited the DNA damage induced by either β-apo-8’-carotenal alone or a carotenoids combined wiht BaP. Quercetin also decreased the levels of CYP1A2 protein induced by β-apo-8’-carotenal alone or β-carotene combined with BaP. In addition, quercetin also suppressed the harmful effects induced by β-apo-8’-carotenal alone.
Overall, our study demonstrates that the oxidative product β-apo-8’-carotenal, rather than β-carotene itself, induces DNA damage and lipid peroxidation and that the aldehyde enhances CYP1A2 expression. β-carotene but not β-apo-8’- carotenal at low doses slightly prevents DNA damage induced by BaP. Quercetin can inhibit the damage induced by β-apo-8’-carotenal and thus enhance the safety of β-carotene.
目次........................................................ Ⅰ
縮寫表...................................................... Ⅳ
中文摘要................................................... Ⅶ
英文摘要................................................... Ⅸ
1. 前言....................................................... 1
1.1 緒論....................................................... 1
1.2 β-胡蘿蔔素................................................. 3
1.3 β-Apo-8’-carotenal........................................... 5
1.4 Benzo[a]pyrene (BaP) ........................................ 7
1.5 類黃酮..................................................... 9
1.6 Cytochrome P450........................................... 13
1.7 A549細胞株( Human lung adenocarcinoma cell line) .............. 17
1.8 研究目標.................................................. 17
1.9 實驗架構.................................................. 18

2. 材料與方法.............................................. 19
2.1 材料...................................................... 19
2.1.1儀器................................................. 19
2.1.2藥品................................................. 19
2.2 方法...................................................... 23
2.2.1 細胞解凍與保存...................................... 23
2.2.2 A549細胞培養....................................... 23
2.2.3 細胞的處理.......................................... 23
2.2.3.1 β-胡蘿蔔素、β-apo-8’-carotenal及類黃酮併入細胞... 23
2.2.3.2 Benzo[a]pyrene (BaP)處理........................ 24
2.2.4 DNA傷害測定-Comet assay (single cell gel electrophoresis assay) .............................................. 24
2.2.5 脂質過氧化測定(Thiobarbituric acid-reactive substances,
TBARs).............................................. 25
2.2.6 西方墨點法(Western blotting) ........................... 26
2.2.6.1 細胞蛋白質的萃取.............................. 26
2.2.6.2 蛋白質濃度測定................................ 26
2.2.6.3 電泳分析...................................... 27
2.2.6.4 轉印分析...................................... 27
2.2.6.5 Blocking、添加抗體及冷光分析................... 27
2.2.7 β-胡蘿蔔素含量分析................................... 28
2.2.8 β-胡蘿蔔素代謝產物含量分析........................... 28 2.2.9 統計分析............................................ 29

3.第一部份結果與討論..................................... 30
3.1 BC與AC對誘發細胞DNA斷裂的影響.................... 30
3.2 BC與AC對誘發細胞脂質過氧化的影響................... 31
3.3 BC與AC對誘發細胞cytochrome P450 (CYP) 1A2表現
的影響................................................ 31
3.4 1-Aminobenzotriazole (ABT)對細胞DNA斷裂的影響......... 32
3.5 BaP對細胞中BC的代謝產物retinoic acid (RA)濃度之影響.... 32
3.6 討論.................................................. 33
圖表......................................................... 36

4.第二部分結果與討論..................................... 44
4.1 類黃酮抑制DNA傷害................................. 44
4.2 類黃酮抑制CYP1A2的表現............................. 44
4.3 Quercetin對細胞中BC濃度之影響....................... 45
4.4 討論.................................................. 46
圖表......................................................... 48

5. 結論..................................................... 54
6. 參考文獻................................................ 55
7. 附錄..................................................... 66
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