第五章 結論與建議
第二節 建議
第一節 結論
本實驗室之前的研究發現眼翳有 BPDE-like DNA adduct[72]，而且其代謝酵 素 CYP1A1 MspI的多型性與所發現 BPDE-like DNA adduct的量相關連[69]，本研 究則進一步發現 CYP1A1 MspI 的基因多型性與眼翳的發生有顯著相關，這個發
現可以讓我們進一步推測眼翳形成的可能致病分子機轉：眼翳除了由廣為所知的 紫外線引起外，環境中的污染物質暴露也可能是造成眼翳的原因。
第二節 建議
本研究分析比較了眼翳組織與正常對照組 PAH代謝酵素 CYP1A1 MspI及
GST M1的基因多型性，發現了 CYP1A1 MspI基因多型性是產生眼翳的危險因
子，然而詳細的作用機轉仍不清楚，可先收集分析正常結膜與眼翳組織
BPDE-like DNA adduct量的差異，或利用體外培養方式培養眼翳及正常結膜上皮 細胞，給予 BaP處理，分析其 BPDE-like DNA adduct量的差異，分析p53突變之 情形、比較眼翳及正常結膜上皮細胞間 CYP1A1 mRNA量及蛋白質量、活性的 異同等等，或可對 CYP1A1 MspI基因多型性與眼翳形成間的機制有進一步的了 解。
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表一 眼翳及正常對照組之性別年齡分布
眼翳 對照組(血液)
男性 136 126
女性 69 80
總數 205 206
年齡 74.2 (52-85) 62.0(55-75)
表二
眼翳及正常對照組之 CYP1A1 MspI 基因多型性分布
Genotype Pterygium
(n=205)
Control
(n=206)
p-valueT/T 68 (33.2%) 89 (43.2%)
T/C 108 (52.7%) 103 (50.0%)
C/C 29 (14.1%) 14 (6.8%) 0.017
Pearson's chi-square test表三
眼翳及正常對照組之 GST M1 基因多型性分布
Genotype Pterygium
(n=205)
Control
(n=206)
p-valuePresent 83(40.5%) 84(40.8%)
Null 122(59.5%) 122(59.2%) 0.952
Pearson's chi-square test表四
CYP1A1 MspI 及 GST M1 多型性各基因型 之眼翳發生率
OR 95%CI p-value
CYP1A1
T/T 1.000 - -
T/C 1.372 0.906-2.079 0.135 C/C 2.711 1.331-5.524 0.006 GST M1
Present 1.000 - -
Null 1.012 0.683-1.500 0.952 Binominal logistic regression test
表五 CYP1A1 及 GST M1 多型性對眼翳 危險因子的多元邏輯迴歸分析
Adjusted
OR 95%CI p-value CYP1A1
Polymorphism/wild type 1.533 1.027-2.290 0.037 GST M1
Null / present type 0.990 0.666-1.471 0.959 Multiple logistic regression test
圖一 眼翳臨床外觀
眼翳pterygium 源於希臘字 pterygos，翼的意思，因為臨床外觀狀如翼
(wing-shaped)，為隆起皺摺的結膜伴有纖維血管(fibrovascular)增生的慢性發炎組 織，翼狀或三角尖端朝向眼角膜，會慢慢往眼角膜上生長，進而遮蔽視線或者造 成散光影響視力。
圖二 CYP1A1 PCR 引子與引子所放大的序列及 MspI 限制酶辨識位置 CYP1A1 基因部分序列如圖，PCR 產物長度由 NCBI 網站上查詢及參考其他文獻
記載，所設計的引子將放大 CYP1A1 第 266 個鹼基至第 605 個鹼基，為一段 340bp 長的片段產物，而限制酶：Msp I 所辨識的序列為一 CCGG 的雙股反向重複序列 (reverse palindrome)，MspI 會切在 CC 之間，CYP1A1 基因上第 400 個鹼基在野 生型(wild type)為 T 鹼基，在變異型則有 C 鹼基(包含同型合子 C/C 及異型合子 T/C)(T6235C)，會使得原本 CTGG 的序列變成 CCGG 序列，且為 CYP1A1 上唯 一的一段CCGG 序列，使得 Msp I 限制酶會將變異型 DNA 序列切成 2 段，一段 長206bp，另一段長 134bp。
圖三 CYP1A1 PCR 產物電泳結果
PCR 產物長度由 NCBI 網站上 引子查詢及參考其他文獻記載得知片段長為 340 bp，總共 205 個眼翳檢體及 206 個對照組血液檢體皆可獲得專一長度的 PCR 產 物片段，並符合預期的340 bp 長。
340 bp
T/T C/C T/C
圖四 CYP1A1 MspI PCR-RFLP 多型性的電泳膠圖結果與判讀
CYP1A1 基因上 T6235C 的多型性，使得以 MspI 限制酶處理後產生長短不同的基
因片段，MspI 限制酶辨識的序列為 CCGG，遇到這樣的序列會從 CC 間將 DNA 序列切斷，所以如果基因型為同型合子野生型T/T 型，其序列為 CTGG，不會被 限制酶切斷，呈現的產物是PCR 產物的原片段長即 340 個 bp；如果基因型是同 型合子變異型C/C 型，其序列為 CCGG，會被限制酶切成 2 段，呈現的產物有 兩種片段長度，即206 bp 及 134 bp 2 種片段長度；若為異型合子變異型 T/C 型，
則340 bp，206bp 及 134 bp 3 種片段長度都有。
340 bp 206 bp 134 bp
圖五 GST M1 PCR 產物的電泳膠圖結果及多型性表現判讀
GST Mu1 gene 是一個約 11kb 長的 gene，所設計出來的專一性引子是用來放大
GST M1 序列內一段 165bp 長的片段，所以 PCR 產物有 2 種結果，一是檢體 DNA
序列沒有缺失性變異，可以放大出標的片段165bp，此即為 present 基因型；另 一種是檢體 GST M1 DNA 序缺失性變異，無引子可辨識序列，沒有 PCR 產物，
此即為 GST M1 null type。
165 bp
附錄
圖一 BaP 與 BPDE(BP-7,8-diol 9,10-epoxide)之代謝
本圖摘自[82]：
Amos, C.I., N.E. Caporaso, and A. Weston, Host factors in lung cancer risk: a review of interdisciplinary studies. Cancer Epidemiol Biomarkers Prev, 1992. 1(6): p.
505-13.
圖二 GST M1 基因的缺失變異原因
GST M1 的基因多型性主要由於整段基因缺失而使其不表現(null allele)，造成此
一變異的原因是因為 GST M1 基因的 2 側各由一段長 4.2kb 幾乎相同的序列所包
圍，GST M1 基因的缺失變異就是由此 2 相似的序列同源重組(homologous recombination) 所造成。
(http://www1.elsevier.com/homepage/sab/oncoserve/cl_mr/parl.htm)