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研究生:李健群
研究生(外文):Chien-Chun
論文名稱:花生四烯酸及二十二碳六烯酸調控苯乙基巴比妥酸誘發大鼠初代肝細胞細胞色素P-450 2B1表現之機制探討
論文名稱(外文):The mechanism of arachidonic acid and docosahexaenoic acid in phenobarbital-induced cytochrome P-450 2B1 expression in rat primary hepatocyte
指導教授:陳暉雯
指導教授(外文):Haw-Wen Chen
學位類別:博士
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:2008
畢業學年度:96
語文別:英文
論文頁數:126
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文獻指出,多元不飽和脂肪酸參與調控多種基因轉錄作用,對於細胞生理、生化及代謝反應扮演關鍵性角色。本實驗室之前建立phenobarbital (PB)誘發大鼠初代肝細胞表現細胞色素P450 2B1 (CYP 2B1)的細胞模式,對後續探討飲食因子如何調控CYP 2B1表現提供了可行的實驗工具。本研究以大鼠初代肝細胞為實驗模式,發現細胞以100 mM n-6多元不飽和脂肪酸arachidonic acid (AA)、linoleic acid (LA)及n-3多元不飽和脂肪酸eicosapentaenoic acid (EPA)、docosahexaenoic acid (DHA)培養時,皆可負向調控PB所誘發之CYP 2B1基因表現,其中以AA和DHA抑制效果最顯著。之前研究證實,增加胞內cAMP濃度可顯著負向調控PB所誘發的大鼠初代肝細胞CYP 2B表現。本研究發現,AA主要是透過其代謝產物PGE2 再經PGE2接受器(EP2)活化cAMP-dependent protein kinase A pathway,進而負向調控PB誘發CYP 2B1基因表現,當細胞以adenylate cyclase 抑制劑SQ22536或PKA抑制劑H89處理時,則可逆轉此一抑制效果。然而,DHA並非透過COX代謝生成的PGE3進行負向調控。因此不排除DHA是透過其它訊息傳遞路徑,進一步影響CYP 2B1基因表現。
核蛋白接受器constitutive androstane receptor (CAR)已被證實在調控解毒代謝基因表現過程中扮演重要角色。先前研究指出,PB誘發人類初代肝細胞CYP 2B6及小鼠初代肝細胞cyp 2b10表現主要是透過CAR的作用;在PB處理模式下,可誘發CAR由細胞質轉移(translocate)至細胞核內,並啟動CAR標的基因CYP 2B表現。本研究發現,PB亦可誘發大鼠初代肝細胞CAR translocation,此一現象與PB處理劑量、時間呈正相關。然而測試的四種多元不飽和脂肪酸,只有預處理DHA可顯著降低CAR translocation。此外,利用電泳流動性轉移分析法(electromobility gel shift assay)及免疫沉澱法(immunoprecipitation)證實,PB誘發CAR 轉移進入細胞核後,CAR先與RXR形成異二聚體(heterodimer)並結合至CYP 2B1基因promoter上PB-responsive enhancer module (PBREM)的NR-1 motif,進而增加CYP 2B1基因表現,然而細胞預處理DHA則顯著抑制PB所誘發的CAR轉錄活化作用(trans-activation)。
上述結果證實n-6與n-3多元不飽和脂肪酸乃是透過不同機制調控PB誘發大鼠初代肝細胞CYP 2B1表現,其中,AA主要是透過代謝產物PGE2 再經EP2活化cAMP-dependent protein kinase A pathway,進而負向調控CYP 2B1基因表現。然而,DHA則是透過減少細胞CAR translocation達到此一負向調控作用。


Rat hepatocyte cytochrome P-450 2B1 (CYP 2B1) expression is modulated by dietary fatty acids and prostaglandin E2 (PGE2). Individual n-6 and n-3 polyunsaturated fatty acids (PUFAs), specifically, arachidonic acid (AA), linoleic acid (LA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), were used to determine their effects on CYP 2B1 expression induced by phenobarbital (PB) in rat primary hepatocytes. PB-induced CYP 2B1 expression was down-regulated by n-6 and n-3 PUFAs, especially AA and DHA. PGE2, a fatty acid metabolite, but not PGE3, down-regulated CYP 2B1 expression induced by PB in rat primary hepatocytes through the EP2 receptor. PGE2 increased the intracellular cAMP level and led to the activation of protein kinase A (PKA). It has been shown that increased cAMP suppresses the induction of CYP 2B1 by PB in rat primary hepatocyte cultures. Suppression of cAMP production by SQ22536, an adenylate cyclase inhibitor, and inhibition of PKA by H-89, resulted in reversion of the down-regulation of CYP 2B1 expression by AA and PGE2 in the presence of PB. PGE2 and the cAMP-dependent PKA pathway are thus involved in the down-regulation of PB-induced CYP 2B1 expression by AA.
The mechanism for the down-regulation of PB-induced CYP 2B1 expression by AA has been delineated; however, the mechanism for this down-regulation by DHA was previously unknown. Constitutive androstane receptor (CAR) was shown to play a crucial role in metabolizing enzyme expression. PB induction of human CYP 2B6 and mouse cyp 2b10 was shown to mediated by CAR. In addition to prostaglandin and the downstream pathways of cAMP and PKA, CAR may be involved in the down-regulation of PB-induced CYP 2B1 expression by PUFAs. PB triggered the translocation of CAR from the cytosol into the nucleus in a dose-dependent and time-dependent manner, and CAR distribution in rat primary hepatocytes was significantly affected by DHA. DHA treatment decreased PB-inducible accumulation of CAR in the nuclear fraction and increased it in the cytosolic fraction. The down-regulation of CYP 2B1 expression by DHA occurred in a dose-dependent manner, and a similar pattern was found for the nuclear accumulation of CAR. The results of immunoprecipitation showed a CAR/RXR heterodimer bound to nuclear receptor binding site 1 (NR-1) of the PB-responsive enhancer module (PBREM) of the CYP 2B1 gene. The EMSA results showed that PB-induced CAR binding to NR-1 was attenuated by DHA. These results suggest that attenuation of CAR translocation and subsequent binding to NR-1 are mechanisms for the down-regulation of PB-induced CYP 2B1 expression by DHA.
In summary, PB-induced CYP 2B1 expression was down-regulated by n-6 and n-3 PUFAs through different pathways. PGE2, EP2, and the cAMP- dependent PKA pathways are involved in the down-regulation of CYP 2B1 expression by AA, whereas the down-regulation by DHA is through attenuation of CAR translocation.

Contents


Abbreviations ··························· I
中文摘要 ··························.····· III
Abstract ································ V
General Introduction ·············.······ 1
Objectives and hypothesis ··············· 19

Chapter Ι
Prostaglandin E2 down-regulation of cytochrome P-450 2B1 expression induced by phenobarbital is through EP2 receptor in rat hepatocytes.
(Biochem. Biophys. Res. Commun. 2005, 327: 424-430) ··34

Chapter ΙΙ
(n-6) and (n-3) Polyunsaturated fatty acids down-regulate cytochrome P-450 2B1 gene expression induced by phenobarbital in primary rat hepatocytes. (J. Nutr. Biochem. 2006, 17: 707-715) ························· 58

Chapter ΙΙΙ
DHA down-regulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes by attenuating CAR translocation.
(Toxicol. Appl. Pharmacol. 2007, 225: 329-336) ······ 89

Overall discussion and conclusion ·················..120

個人資料表 ······································..· 125


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