| 摘要: | 已有證據顯示，魚油可抑制乳癌及結腸癌的形成，至於魚油與肝癌的關係，也有資料指出高魚油飲食組相較與高玉米油飲食組可減少Diethylnitrosamine (DEN)-phenobarbital (PB)模式下所產生的肝前癌細胞，但魚油抑制癌症的機制仍不清楚。魚油因富含Eicosapentaenoic acid（EPA）及Docosahexaenoic（DHA），因此多食魚油將改變組織中脂肪酸組成，進而改變脂肪酸代謝產物，減少Prostaglandin E/sub 2/及Prostaglandin F/sub 2α/（PGF/sub 2α/）生合成但該模式下並無充分證據支持PGF/sub 2α/與魚油抑制肝前癌細胞形成有關。由於相當多研究指出Peroxisome proliferator-activated receptors (PPARs)是脂質調控細胞代謝與細胞分化的重要調節者，因此是否飲食油脂調節肝前癌細胞生成與其活化PPAR-α有關，值得進一步研究。PPARs，是Ligand-activated transcription factors，而在鼠類肝臟中以PPAR-α較多。PPARs被PPAR活化劑活化後，將進而調節PPAR反應基因轉錄作用（PPAR response gene mRNA transcription）。雖然脂肪酸可與PPAR-α結合，但不同脂肪酸與PPAR-α間的親和性並不一致，例如老鼠肝實質細胞（Hepatic parenchymal cells）PPAR-α可被EPA活化，但亞麻油酸，次亞麻油酸和花生油四烯酸則無此作用。雖然EPA比其他脂肪酸對PPAR-α的活性強，但與一降血脂質藥物，WY-14,643相較下，WY-14,643與PPAR-α間的親和力又較EPA強多了。雖然長期給予鼠類WY-14,643可誘發肝癌之形成，但是證據也顯示與PPAR-α親和力較弱之Activators，例如：亞麻油酸和花生油四烯酸，以及Perfluorinated decanoate（脂肪酸衍生物）對於DEN誘發鼠類肝癌形成並沒有影響或影響很小，因此我們假設這可能與其對PPAR-response genes mRNA轉錄的強弱有關。所以本計畫我們假設，魚油與玉米油可經由與PPAR-α相關機制來影響由DEN-PB模式下所產生的肝前癌細胞，同時其作用機制可能與WY-14,643誘發肝癌不同。與以往實驗結果一致，與餵食玉米油組老鼠相比較，餵食玉米油組老鼠肝臟中GSH Foci顯著減少，而餵食Clofibrate組老鼠肝臟中GSH Foci顯著增加。但是餵食魚油組老鼠肝臟中GST-P之mRNA及蛋白質量較餵食玉米油組老鼠及餵食Clofibrate組老鼠高。PPAR Response genes例如CYP4A1，L-FABP之mRNA在餵食魚油組老鼠肝臟中量大於餵食玉米油組老鼠及餵食Clofibrate組老鼠。CYP4A1蛋白質量亦與mRNA結果相似，餵食魚油組老鼠肝臟中大於餵食玉米油組老鼠及餵食Clofibrate組老鼠。
Previous results have shown that dietary fish oil can inhibit breast and colon carcinogenesis. Data from our laboratory have shown that dietary fish oil can decrease rat liver foci formation by using the diethylnitrosamine (DEN)-phenobarbital (PB) model when compared with dietary corn oil. However, the chemopreventive mechanisms of fish oil are not fully understood. Fish oil is high in n-3 fatty acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) so it could modify the fatty acid distribution in tissues. Furthermore, fish oil could modify fatty acid metabolites especially, prostaglandin E/sub 2/ and prostaglandin F/sub 2α/ (PGF/sub 2α/). In rat livers, fish oil decreased the PGF/sub 2α/ synthesis when compared with corn oil and the addition of tumor promoter PB had not effect on the PGF/sub 2α/ synthesis. In this project we would like to explore the possible mechanisms of inhibitory capacity of dietary fish oil in of rat liver foci formation by the diethylnitrosamine-phenobarbital model. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and PPAR-α is the predominant isoform in rodent livers. PPARs could be activated by their ligands or activators and then modify the PPAR response gene mRNA expression. WY-14,643 is a potent ligand of PPAR-α. When compared with WY-14,643 the polyunsaturated fatty acids such as linoleic acid (LA), EPA and DHA are weak activator of PPAR-α. In rat hepatic parenchymal cells, the PPAR-A is activated by EPA but not by LA, linolenic acid, or arachidonic acid (AA). Since LA, AA and the fatty acid derivative, perfluorinated decanoate are weaker than WY-14,643 to bind to PPAR-α, unlike WY-14,643, they may not influence or have little effect on promoting liver cancinogenesis initiated by DEN. This may be due to different capacity of induction of PPAR response gene mRNA expression between strong and weak PPAR-α ligands (or activators). We hypothesize the because amount of PPAR response gene mRNA expression induced by LA and EPA are lower than by WY-14,643, fish oil and corn oil will not induce rodent liver cancer. Furthermore, fish oil and corn oil could influence liver foci formation through a PPAR-α related mechanism. Dietary fish oil increased the CYP4A1 and L-FABP, PPAR response genes, mRNA expression compared with dietary corn oil and clofibrate. However, Dietary fish oil decrease the liver GSH foci synthesis compared with dietary corn oil and clofibrate. The relationship between fish oil and liver carcinogenesis needs more future study. |
