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研究生:王雅靜
研究生(外文):Ya-Ching Wang
論文名稱:以細胞色素CytochromeP4502D6(CYP2D6)酵素測試不同致癌物質之生物活性
論文名稱(外文):Bioactivation of Various Carcinogens by the Cytochrome P4502D6 (CYP2D6)Enzyme
指導教授:李益謙李益謙引用關係
指導教授(外文):Eric I-chian Li
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:81
中文關鍵詞:細胞色素P450
外文關鍵詞:4-aminobiphenylmethyl-n-butyl-nitrosaminebenzo[a]pyreneethylmethanesulfonatecyclophosphamidecytochrome P450 2D6cytochrome P4504-(N-methyl -N-nitrosamine)-1-(3-pyridyl-1-butan
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中文摘要

外來物質 (xenobiotics),例如藥物、食品添加物、致癌物質 (carcinogens) 以及環境化合物等,進入人體後在體內會進行吸收、分佈、代謝與排除的作用,而後堆積在體內或排除至體外。細胞色素P450 (cytochrome P450) 為體內代謝外來物質最重要的酵素之一。一般而言,外來物質經過P450的代謝毒性會降低,但有時經由cytochrome P450代謝後,反而會將外來物質毒性變成對人體具有致突變性 (mutagenic)或致癌性 (carcinogenic)的物質。因此,cytochrome P450同時具有解毒及代謝活化的雙重角色。環境致癌物在體內的代謝途徑往往不能精確掌握,有必要藉助含有特殊cytochrome P450基因 (gene)的離體細胞來測知其代謝作用。CYP2D6為cytochrome P450超級家族 (superfamily)中的一個成員。1977年有研究指出CYP2D6代謝藥物的能力在個體之間有很大的差異,具有基因的多型性 (polymorphism)現象。中國人族群CYP2D6的主要等位基因 (allele)含T188、C4268的變異。高加索人族群CYP2D6的主要等位基因含C188、G4268的變異。由於不同遺傳變異可造成CYP2D6代謝能力改變,為了更進一步了解這些變異對致癌物質代謝的影響,本實驗以中國田鼠肺纖維細胞V79 (Chinese hamster fibroblast cells)為模型,建構國人特有CYP2D6等位基因永久細胞株 (V79/CYP2D6 cell lines),以及其對照空白質體細胞株,來測試一些由多種cytochrome P450代謝的致癌物質,例如:4-(methyl- nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)、4-Aminobiphenyl (4-ABP)、Benzo[a]pyrene (B[a]P)、Methyl-n-butyl-nitrosamine (MBN)等環境中常見致癌物質,是否經CYP2D6代謝,並且觀察Na+,K+-ATPase基因、thymidylate synthetase基因之突變頻率是否增高。由本實驗結果可知V79/2D6-w.t.、V79/2D6-C4268因具有正常功能之CYP2D6,所以對NNK及MBN等致癌物質之感受性較高,反之V79/2D6-T188因CYP2D6在DNA序列188位置產生變異,而降低對NNK及MBN等致癌物質之感受性。
Abstract

Over 40 drugs are known to be the substrates of the cytochrome P450 enzyme, CYP2D6. Individuals that are metabolically competent are referred to as extensive metabolizers (EMs), and those that are incapable of metabolizing these drugs the poor metabolizers (PMs). This polymorphism shows marked ethnic differences in its frequency: 5 to 10 % of Caucasians and 1.6% Chinese are CYP2D6 deficient due to mutations. In Chinese especially there are two codons in CYP2D6 that are polymorphic: codon 34 (Pro→Ser) and codon 486 (Ser→Thr), more than 50% of the Chinese subjects have both mutations. Some epidemiological studies have linked EMs phenotype to increased lung cancer risks in smokers. The polymorphism in CYP2D6 is thus more than just important in drug therapy, it may also play a role in cancer susceptibility. Our strategy is to construct expression vectors (pRC/CMV) with different CYP2D6 mutations and stably express in Chinese hamster V79 fibroblast cells for mutation studies. V79 cell line itself does not exhibit endogenous cytochrome P450 enzymes. The constructed V79 cells harboring different CYP2D6 alleles are then challenged with carcinogens benzo[a]pyrene, 4-aminophenyl, MBN (methyl-n-butyl-nitrosamine),and NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Using thymidylate synthetase gene and Na+,K+- ATPase gene as mutation markers, we find there are differential mutation effects of CYP2D6 polymorphism on the carcinogens tested. The sensitivities of V79/2D6-w.t. and V79/2D6-C4268 cell lines with normal CYP2D6 enzyme activities function to NNK and MBN are high, as judged by mutation frequencies of two mutation markers. However the sensitivity of V79/2D6-T188 cell line with mutation of C188 in CYP2D6 DNA sequence to NNK and MBN decrease significantly.
目錄

第一章 緒論…………………………………1
第二章 實驗目的……………………………6
第三章 實驗材料……………………………7
第四章 實驗方法……………………………10
第五章 實驗結果……………………………25
第六章 討論…………………………………37
參考文獻………………………………………44
圖表……………………………………………53
自述……………………………………………81
參考文獻

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