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研究生:黃碩彥
研究生(外文):Shuo-Yan
論文名稱:Quercetin抑制benzo[a]pyrene合併4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone或β-胡蘿蔔素在體內誘發的促氧化及促發炎效應
論文名稱(外文):Quercetin suppresses the pro-oxidative and pro-inflammatory effects of benzo[a]pyrene in combination with 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone or β-carotene in vivo
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:2010
畢業學年度:98
語文別:中文
論文頁數:99
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Quercetin是一種廣泛存在於蔬果中的類黃酮化物。許多體外實驗顯示,quercetin具有抗氧化及抗發炎等許多生理活性,因此能抑制香菸煙霧中的致癌物質單獨或是合併β-胡蘿蔔素所造成的傷害。然而,quercetin經由phaseⅡ酵素代謝後,是以conjugated metabolites型式而非其aglycone存在於血漿中,且體外研究觀察到的現象常未能真正反應其在體內的重要性。因此,本實驗預計以Balb/c小鼠及蒙古沙鼠做為實驗模式,分為兩部分進行體內試驗,探討quercetin在體內的抗氧化及抗發炎效應。
第一部分
我們研究不同濃度的quercetin(50 mg/kg body wt (LQ)、500 mg/kg body wt (HQ))對Benzo[a]pyrene (Bap)合併4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)所誘發Balb/c小鼠體內氧化壓力及促發炎激素分泌的影響。動物隨機分為六組(6隻/組):(1)控制組(2)LQ(3)HQ(4)Bap+NNK(5)Bap+NNK+LQ(6)Bap+NNK+HQ,共為期三個月。實驗期間,quercetin經由管灌餵食,每週二次,Bap(5 mg/kg body wt)及NNK(4 mg/kg body wt)經由腹腔注射每週一次。結果顯示,quercetin管餵1-2小時後,Balb/c小鼠血漿中quercetin glucuronide及sulfate結合的代謝產物總濃度達到最高,LQ及HQ組分別約為2.3及4 μM。LQ顯著地抑制Bap合併NNK造成的內生性DNA傷害; LQ和HQ也能顯著降低Bap合併Bap+NNK+LQ/HQ也顯著的低於Bap合併NNK處理組。且Bap合併NNK顯著地增加肺灌流液及肝臟中TNF-α及IL-1β的分泌, quercetin處理則以劑量依賴效應明顯地降低Bap合併NNK所造成的影響。西方墨點法顯示quercetin抑制JNK及c-Jun蛋白的磷酸化。以上結果顯示,補充quercetin能降低 Bap合併NNK所造成Balb/c小鼠體內的促氧化及促發炎效應。
第二部分
此部分我們探討quercetin是否降低β-胡蘿蔔素在Bap誘發下對於蒙古沙鼠體內的傷害效應。同時我們也將比較quercetin與維生素C合併維生素E(C+E)的效果。實驗期間,沙鼠以管灌單獨餵食β-胡蘿蔔素(10 mg/kg body wt),或是合併quercetin(50 mg/kg body wt (LQ)或100 mg/kg body wt (HQ))或是合併維生素C(13 mg/kg body wt)+維生素E(92 mg/kg body wt),每週三次,為期六個月。實驗前二個月期間,除控制組以外,其餘組別每週一次經由氣管滴入(intratracheal instillation)Bap。結果顯示,Bap處理組顯著地增加白血球內生性DNA傷害、H2O2-lesion及血漿中TBARs濃度。BC處理明顯地促進Bap所誘發的H2O2-lesion,而LQ或HQ合併BC則明顯的抑制Bap所造成的氧化傷害。Bap處理組其肺部總抗氧化力、穀胱甘肽含量及超氧歧化酶、觸酶及穀胱甘肽過氧化酵素活性顯著低於控制組。與Bap處理組相比,除超氧歧化酶外,BC增加了上述測定值的量或活性, LQ合併BC處理組的效應則多與BC組相似,HQ處理組大多顯著地較BC單獨處理組增加,且效果與C+E相似。在發炎指標方面,Bap處理增加了血漿或肺灌流液中IL-6 、IL-1β及TNF-α的分泌,BC則有促進Bap的促發炎激素分泌的趨勢,然而LQ/HQ合併BC處理則具抑制Bap影響的趨勢。與LQ/HQ合併BC組相較下,維生素C合併維生素E的服用在抗發炎的效果與quercetin相似。綜合以上結果顯示,quercetin經由體內代謝後的產物能與β-胡蘿蔔素交互作用,而quercetin的此一效果可能與其代謝產物的抗氧化及抗發炎效果有關。而其確實的機制仍需要進一步的研究。


Quercetin, a flavonoid, is found ubiquitously in vegetables and fruits. Several in vitro studies have shown that quercetin suppresses the harmful effects of cigarette smoking-associated carcinogens alone or in combination with β-carotene through several mechanisms, including antioxidative and anti-inflammatory activity. However, quercetin conjugated metabolites rather than quercetin aglycone is present in human plasma because of its efficient phase II metabolism. Whether those effects of quercetin observed in vitro are significant in vivo is unclear. Therefore, using Balb/c mice and Mongolian gerbils, the thesis work was divided into two parts to study the influence of quercetin in vivo.

Part I
We investigated the preventive effects of quercetin at 50 mg/kg wt body (LQ) or 500 mg/kg body wt (HQ) against benzo[a]pyrene (Bap)+ 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced oxidative stress and the secretion of proinflammatory cytokines in Balb/c mice. The animals were randomly assigned to following six groups (n = 6/group): (1)control, (2) LQ, (3) HQ, (4) Bap+NNK, (5) Bap+NNK+LO, (6) Bap+NNK+HQ. Quercetin was given to animals by gavage 2 times/week for 3 months; whereas Bap+ NNK exposure was performed by intraperitoneal injection 1 time/week. HPLC assay showed that at 1-2 h after oral administration of quercetin, the sum concentration of plasma glucuronidated and sulfated quercetin reached the maximum (about 2.3 and 4 μM at LQ, and HQ group, respectively). LQ significantly reduced Bap+NNK-induced endogenous DNA damage, whereas two doses of qeurcetin significantly reduced Bap+NNK -increased H2O2-lesion in a dose-dependent manner. The TBARs levels in Bap+NNK+LQ and +HQ group were also significantly lower than that of Bap+NNK. In addition, Bap+NNK significantly increased the levels of TNF-α and IL-1βin bronchoalveolar lavage fluid and liver, while quercetin significantly decreased the effects of Bap+NNK in a dose-dependent manner. Such effects of quercetin may be associated with the regulation of c-Jun and JNK activation, because quercetin also decreased the phosphorylation of c-Jun and JNK induced by Bap+NNK. These results suggest that quercetin attenuates the pro-oxidative and pro-inflammatory effects of Bap+NNK in Balb/c mice.

Part II
In this part, we investigated whether quercetin decrease the effects ofβ-carotene induced by Bap in Mongolian gerbils (gerbils). We also compared the effects of quercetin with that of vitamin C (C)+vitamin E (E). The gerbils were given β-carotene (BC; 10 mg/kg body wt) alone or in comebination with quercetin (50 mg/kg body wt for LQ, or 100 mg/kg body wt for HQ) or vitamin C (13 mg/kg body wt) +vitamin E(92 mg/kg body wt) by gavage 3 times/week for 6 months. At the firs 2 months, expect for control group, the gerbils were exposed to Bap by intratracheal instillation 1 time/week. As expected, Bap exposure significantly increased endogenous DNA damage and H2O2-lesion of while blood cells and TBRAs concentration in plasma. BC enhanced the effect of Bap on increase of H2O2-lesion, while LQ/HQ+BC significantly suppressed the effect of Bap mentioned above. The total antioxidant activity, the level of glutathione and the activity of superoxide dimutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in lungs of gerbils in Bap-exposed group were significantly lower than those of control group. Compared with Bap exposure group, BC increased the levels or activity of the parameters mentioned above except for SOD; the effects of LQ/HQ+BC were better than or similar to that of BC alone in these parameters. LQ/HQ+BC also significantly increased the activity of SOD. In addition, Bap exposure significantly or slightly increased the concentration of IL-6, IL-1β and TNF-α in plasma or bronchoalveolar lavage fluid, respectively. BC tended to enhance such effects of Bap while LQ/HQ+BC tended to decreased the effects of Bap. Compared with BC+C+E, LQ/HQ+BC had similar effects on suppressing the proinflammatory effect of BC. These results demonstrated that supplemental quercetin interacts withβ-carotene in vivo. The antioxidative and anti-inflammatory effects of quercetin metabolites may be contributed to such effect of quercetin. Further studies are warranted to investigate the precise mechanisms underlying these effects of quercetin in vivo.

縮寫表………………………………………………………………….Ⅰ
中文摘要……………………………………………………………….Ⅲ
英文摘要……………………………………………………………….Ⅵ
一、 前言
1. 序論…………………………………………………………………...1
2. 文獻探討……………….......................................................................3
2.1槲黃酮(Quercetin)…………………………………………………3
2.2β-胡蘿蔔素(β- carotene)…………………………………………….7
2.3 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)及
Benzo[a]pyrene (Bap)……………………………………………….11
2.4氧化壓力……..……………………………………………………...15
2.5抗氧化酵素…..……………………………………………………...17
2.5.1超氧歧化酶(superoxide dismutase)…..………………………..17
2.5.2觸酶(catalase)…….…………………………………………….18
2.5.3榖胱甘肽過氧化酵素(glutathione peroxide)……………..……18
2.6維生素C ……………………..……………………………………20
2.7維生素E ……………………..……………………………………21
2.8 Activator protein-1(AP-1)及Mitogen-activated-protein kinase (
MAP kinase)…………………….…………………………………..23

2.9細胞激素……………..……………………………………………...25
2.10研究動機與目的…..……………….………………………………27
2.11實驗架構…..……………………………………………………….28
二、 材料與方法
2.1材料..………….…………………….……………………………….32
2.1.1儀器…………….….………………………………………………32
2.1.2藥品…………….………………………………………………….33
2.2方法…..………..…………………………………………………….36
2.2.1實驗動物飼育及處理…..…………………………………………36
2.2.2肺灌流液(Brochoalveolan Lavage)…..…………………………..37
2.2.3細胞激素分析…..………………………………….……………...37
2.2.4組織均質液樣品製備……..……………………………………....38
2.2.5脂質過氧化分析(TBARs)…….………………………………….39
2.2.6總抗氧化力分析(Trolox equivalent antioxidant capacity)……....39
2.2.7榖胱甘肽分析(glutathione assay)….…….………………………40
2.2.8榖胱甘肽過氧化酵素分析(glutathione peroxidase assay)..……..41
2.2.9觸酶分析(catalase assay)…..…………………………….………42
2.2.10超氧歧化酶分析(superoxide distumase assay)………………42
2.2.11 DNA傷害分析(comet assay)………………………….……….42

2.2.12 Balb/c小鼠血漿中quercetin代謝總濃度分析………….…...…44
2.2.13西方墨點分析法(Western blot assay)………..………………..45
2.2.14統計分析………...……………………………………………….49
三、結果與討論
3.1第一部分結果…………..…………………………………………...50
3.2第一部分討論……………………..………………………………...53
圖一、Quercetin在Balb/c小鼠體內的濃度於管餵後隨時間改變的變
化量…...……………..……………………..…...………………57
圖二、Quercetin對於NNK合併Bap所誘發的Balb/c小鼠之白血球
DNA傷害影響.…………….………………..…………...……..58
圖三、Quercetin對於NNK合併Bap所誘發Balb/c小鼠血漿中脂質過
氧化的影響...…………………..……………………..………...59
圖四、Quercetin對於NNK合併Bap誘發Balb/c小鼠不同組織中細胞
激素TNF-α之含量….……………..………………………..….60
圖五、Quercetin對於NNK合併Bap誘發Balb/c小鼠不同組織中細胞
激素IL-1β之含量…………..………………..…………………62
圖六、Quercetin對於NNK合併Bap誘發Balb/c小鼠肺組織中JNK磷酸化的影響………………..……………………..…………..64
圖七、Quercetin對於NNK合併Bap誘發Balb/c小鼠肺臟中c-Jun磷

酸化的影響…………………………………………………..…65
3.3第二部分結果……………..………………………………………...66
3.4第二部分討論……………………..………………………………...67
圖八、沙鼠白血球DNA傷害的情形….…………………………..…..73
圖九、沙鼠血漿中脂質過氧化的程度….……….……………………..74
圖十、沙鼠肺部總抗氧化力的情形…..………………………………..75
圖十一、沙鼠肺部超氧歧化酶的活性…………………………………76
圖十二、沙鼠肺部觸酶的活性…..……………………………………..77
圖十三、沙鼠肺部穀胱甘肽過氧化酵素的活性……………………...78
圖十四、沙鼠肺部穀胱甘肽的含量……….…………………………..79
圖十五、沙鼠血漿及肺灌流液中細胞激素IL-6的含量………………80
圖十六、沙鼠血漿及肺灌流液中細胞激素IL-1β的含量……………..81
圖十七、沙鼠血漿及肺灌流液中細胞激素TNF-α的含量………..…..82
四、結論………………………………………………………………...83
五、參考文獻…………………………………………………………....84
六、附錄…………………………………………………………………99

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