- 學位論文
探討5-去甲基川陳皮素對於苯駢芘代謝之影響
The effects of 5-demethylnobiletin on benzo[a]pyrene metabolism
摘要
多環芳香烴 (Polycyclic aromatic hydrocarbons, PAHs) 為已知存在於環境中的一類汙染物，主要由有機物之不完全燃燒所產生，其存在的環境包含空氣、土壤、水等。目前已有許多研究證實部分多環芳香烴對於人體具有致突變性與致癌性，由於食安意識的抬頭，隨飲食途徑攝入之多環芳香烴逐漸受到重視，而其中又以苯駢芘 (Benzo[a]pyrene, BaP) 最具代表性。苯駢芘進入人體後會藉由生物體中外生性物質代謝 (Xenobiotic metabolism) 的一期反應酵素如細胞色素1A1 (Cytochrome P450 1A1, CYP1A1) 與細胞色素1B1 (Cytochrome P450 1B1, CYP1B1) 來進行生物轉換作用，形成反應性較高的苯駢芘二醇環氧化物 (Benzo[a]pyrene diol epoxide, BPDE)，其具有與DNA結合成BPDE-DNA加合物並造成基因突變的能力。轉換後之苯駢芘代謝物可再經由二期反應酵素作用，進行去毒性的程序並將去毒後之代謝物排出體外。許多研究發現柑橘類果皮當中含有的多甲氧基黃酮具有抗氧化、抗發炎、抗癌的能力，而5-去甲基川陳皮素 (5-demethylnobiletin, 5-DMNB) 亦為其中之一，5-去甲基川陳皮素主要是柑橘果皮中的川陳皮素經過自然水解而形成，於長期儲存之果皮含量通常會較新鮮果皮多，有文獻指出其具有抗發炎、抗癌等生物活性。本實驗想藉由動物模式與細胞模式去了解5-去甲基川陳皮素對於飲食途徑攝入之苯駢芘代謝是否造成影響。結果顯示給予了5-去甲基川陳皮素後能夠抑制因苯駢芘所誘導而活化之芳香烴受體訊號傳遞路徑，進而改變一期反應酵素中細胞色素1B1之生成，另外也能夠增加二期反應酵素裡Glutathione S-transferases與UDP-glucuronosyltransferase之基因表現，使生物體具有更佳的去毒性能力。綜合以上原因，5-去甲基川陳皮素能夠讓BPDE與DNA結合產生之BPDE-DNA加合物減少，降低因BaP代謝而產生之致突變性或致癌性，達到預防癌症起始階段之功效。
並列摘要
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants and formed by incomplete combustion of organic matter or charred food. Many studies indicated that PAHs have gene-mutated activity and carcinogenic properties. Among these PAHs, benzo[a]pyrene (BaP) is the most well-known PAHs, and it is classified to group I carcinogen by IARC. Dietary BaP could be metabolized by phase I enzymes, cytochrome P450s (CYPs) such as CYP1A1 and CYP1B1. After metabolization, it could transform the BaP to benzo[a]pyrene diol epoxide (BPDE), and then combine with DNA to form BPDE-DNA adducts, which cause the initiation of cancer. Glutathione S-transferase (GST) and UDP-glucuronosyltransferase (UGT) are phase II enzymes that can conjugate with BaP metabolites and excrete them from body. 5-demethylnobiletin (5-DMNB) is a phytochemical which found in citrus peels, especially in long-storage citrus peels. Researches indicated that 5-DMNB had anti-inflammatory and anti-cancer ability. This study will show that 5-DMNB can change the metabolism of BaP by decreased CYP1B1 level and upregulated the GST and UGT expression, and then decrease BPDE-DNA adducts levels. In conclusion, 5-DMNB can decrease the toxicity of BaP and it maybe have the prevention effect of cancer caused by BaP.