臺灣博碩士論文加值系統

摘 要

Cytochrome P450 (CYPs)是一群帶有heme基質的monooxygenase酵素蛋白，參與了許多外生性毒化物、藥物以及內生性脂質、固醇類荷爾蒙的氧化代謝與合成之工作。其中對外生性毒物代謝之功能，主要是以CYP1、CYP2、CYP3與CYP4類蛋白負責，而人類60%以上的藥物更是經由CYP3酵素進行代謝作用。目前在斑馬魚中共找到二個CYP3家族成員，分別是CYP3A65及CYP3C1。先前對CYP3A65之研究結果發現，該基因與其它物種的CYP3基因相似，在成魚中主要於腸道與肝臟表現，而於胚胎時期自剛孵化的仔魚中開始於腸道專一性表現。除了與哺乳動物CYP3A基因相似，CYP3A65會受到rifampicin (RIF)與dexamethasone (DEX)的刺激增加其基因的表現，此外，CYP3A65亦會受到戴奧辛(TCDD)的刺激，誘發腸道細胞大量表現此基因，顯示此基因有較哺乳動物CYP3A基因複雜之調控機制(Tseng et al., 2005)。在本實驗中，針對斑馬魚CYP3家族另一成員CYP3C1基因之表現一藥物敏感性和基因調控機制進行一系列的探討，並與CYP3A65進行比較。在蛋白質序列上，比對兩者胺基酸序列，發現有48％的相同度及61％的相似度，顯示兩者間有相當程度的相似性。
針對CYP3C1基因表現的研究發現，CYP3C1與CYP3A65相似，在剛孵化的仔魚中，開始於腸道大量表現。而與斑馬魚CYP3A65基因不同的是從在胚胎發育早期起，斑馬魚CYP3C1基因即在頭部持續性表現。其次，觀察斑馬魚CYP3C1基因對藥物之敏感性，發現在胚胎發育時期，CYP3C1在腦部之表現並未受 RIF、DEX及戴奧辛(TCDD)處理所影響，而在孵化後的仔魚中，CYP3C1基因在腸道的表現則對上述之化合物有些微的反應，但並不顯著。已知哺乳類CYP3A基因調控是透過高度保守的PXR::RXR信息傳遞系統，而對斑馬魚CYP3A65及CYP3C1之基因調控機制進行發現，利用PXR及AHR2的antisense morpholino oligonucleotide分別阻斷胚胎內的PXR::RXR及AHR2::ARNT訊息傳遞系統，會造成CYP3A65基因在胚胎發育時期受到抑制，而CYP3C1基因則不受兩者所調控。另一方面，斑馬魚PXR基因與CYP3A65及CYP3C1基因表現方式相似，在剛孵化的仔魚中開始於腸道表現，且在胚胎發育早期就已開始於頭部表現。進一步阻斷胚胎內AHR2::ARNT訊息傳遞系統，發現斑馬魚PXR基因並不受此路徑所調控，顯示TCDD所活化之AHR2::ARNT訊息傳遞系統，並非藉由對PXR基因的調控，參與斑馬魚CYP3A65之基因之調控工作。

Abstract

Cytochrome P450 (CYPs) are a superfamily of heme-containing monooxygenases that metabolize foreign compounds including xenobiotics and drugs, as well as endogenuous compounds such as fatty acid and steroids. Family 1, 2, 3, and 4 are generally designated as drug detoxification enzymes due to their considerable abilities to metabolize xenobiotic compounds. In human, CYP3A isoforms are involved in the metabolism of more than 60% drugs. Up to date, two members of family 3 were identified in zebrafish, CYP3A65 and CYP3C1. Like mammalian CYP3A genes, CYP3A65 mRNA was initially transcribed in the liver and intestine tissues during hatching stages and CYP3A65 transcription in the intestine was enhanced by treatment with the steroid dexamethasone (DEX) or rifampicin (RIF). In addition, the CYP3A65 transcription was also enhanced by treatment with tetrachloro-dibenzo-p-dioxin (TCDD) during early larval stages. Repression of AHR2 translation by antisense morpholino oligonucleotides abrogated both of constitutive and TCDD-stimulated CYP3A65 transcription in larval intestine tissue. This finding revealed that the regulation of CYP3A65 is more complex than mammalian CYP3A genes (Tseng et al., 2005). In this study, I have cloned CYP3C1 gene and its encoded amino acid sequence shares significant similarity with CYP3A65, that is 48％ identity and 61％ similarity. In zebrafish embryo, CYP3C1 mRNA was initially transcribed in the intestine at hatching stage. In early stage, the CYP3C1 mRNA was also constitutively expressed in the head region. Differing from CYP3A65, CYP3C1 transcription was not greatly enhanced by dexamethasone, rifampicin, or TCDD treatment during embryonic stages. In mammals, the CYP3A genes are modulated by the PXR-RXR signaling pathway. Here we showed that the CYP3A65, but not CYP3C1, transcription in the intestine was greatly reduced by repression of PXR or AHR2 translation via applying antisense morpholino oligonucleotides. Neverless, the PXR transcription was not changed by AHR2 repression. It suggests that that the AHR2 signaling pathway plays an essential role in regulation of CYP3A65 transcription which is not controlled by modulation of PXR gene expression.

目 錄
摘要 ------------------------------------------------------------------------------- 1
壹、前言------------------------------------------------------------------------ 5
一、Cytochrome P450s (CYPs)----------------------------------------------- 5
(一) Cytochrome P450s (CYPs) Superfamily--------------------------- 5
(二) CYPs基因對外生性毒化物的敏感性---------------------------- 6
二、Cytochrome P450 3 subfamily (CYP3)-------------------------------- 8
(一) CYP3家族----------------------------------------- -------------------- 8
(二) CYP3A亞家族-------------------------------------------------------- 9
1. CYP3A基因的表現------------------------------------------------ 9
2. CYP3A基因的誘導物種間的差異性--------------------------- 11
3. CYP3A基因誘導的分子機制------------------------------------ 12
三、細胞核受器和CYP3A的誘導反應------------------------------------ 14
(一) 細胞核受器的基本介紹--------------------------------------------- 14
(二) PXR與CAR調節部分CYP基因的轉錄蛋白------------------ 17
(三) PXR基因的選殖----------------------------------------------------- 18
(四) PXR基因表現的組織專一性--------------------------------------- 19
(五) PXR細胞訊息傳遞系統調控CYP3A4--------------------------- 20
1. PXR基因的活化-------------------------------------------------- 20
2. PXR::RXR辨認DNA的特性---------------------------------- 21
3. PXR的下游基因---------------------------------------------------- 22
(六)藥物相互作用---------------------------------------------------------- 23
(七) PXR與CAR的交互作用------------------------------------------- 24
(八) PXR與CAR的分子演化------------------------------------------ 26
四、斑馬魚CYP3 基因------------------------------------------------------ 28
五、研究動機------------------------------------------------------------------- 29
貳、實驗材料與方法-------------------------------------------------- 30
一、實驗材料------------------------------------------------------------------- 30
二、實驗方法------------------------------------------------------------------- 36
A、斑馬魚飼養與受精胚胎之收集------------------------------------ 36
B、各種化合物對斑馬魚胚胎之浸泡試驗--------------------------- 36
C、斑馬魚全量RNA之抽取---------------------------------------- --- 37
D、核酸電泳分析--------------------------------------------------------- 38
E、DNA分子之萃取----------------------------------------------------- 39
F、DNA接合反應-------------------------------------------------------- 40
G、質體轉型--------------------------------------------------------------- 41
H、反轉錄聚合酶連鎖反應--------------------------------------------- 42
I、RNA全覆式原位雜交------------------------------------------------ 43
J、顯微注射 --------------------------------------------------------------- 48
參、實驗結果-------------------------------------------------------------- 50
一、斑馬魚CYP3C1 cDNA的選殖---------------------------------------- 50
二、斑馬魚CYP3C1基因之表現------------------------------------------- 50
三、斑馬魚CYP3C1基因對RIF及DEX之藥物敏感性-------------- 51
四、斑馬魚CYP3C1基因對戴奧辛(TCDD)之敏感性------------------ 52
五、斑馬魚PXR基因之表現------------------------------------------------ 52
六、斑馬魚CYP3基因調控與PXR::RXR訊息傳遞系統之關係----- 53
七、斑馬魚CYP3基因調控與AHR::ARNT訊息傳遞系統之關係--- 54
肆、討論----------------------------------------------------------------------- 55
一、斑馬魚CYP3C1基因的表現-------------------------------------------- 55
二、斑馬魚CYP3基因對藥物之敏感性----------------------------------- 56
三、斑馬魚CYP3及PXR的基因調控------------------------------------- 56
（一）斑馬魚CYP3A65的基因調控--------------------------------------- 56
（二）斑馬魚PXR的基因調控---------------------------------------------- 58
（三）斑馬魚CYP3C1的基因調控----------------------------------------- 58
伍、參考文獻--------------------------------------------------------------- 60
陸、圖表----------------------------------------------------------------------- 78
Table 1：24ng PXR-MO胚胎各時期之平均存活率---------------------- 78
Figure 1：CYP3C1與CYP3A65之胺基酸序列比對--------------------- 79
Figure 2：斑馬魚CYP3C1基因之表現------------------------------------- 80
Figure 3A：斑馬魚胚胎時期CYP3C1基因之表現----------------------- 81
Figure 3B：斑馬魚仔魚時期CYP3C1基因之表現----------------------- 82
Figure 4：斑馬魚CYP3C1基因對Rifampicin之藥物敏感性---------- 83
Figure 5：斑馬魚CYP3C1基因對Dexamethasone之藥物敏感性---- 84
Figure 6：斑馬魚CYP3C1基因對TCDD之敏感性--------------------- 85
Figure 7：斑馬魚PXR與其它物種PXR之胺基酸序列比對----------- 86
Figure 8：斑馬魚胚胎PXR基因之表現------------------------------------ 87
Figure 9A：斑馬魚胚胎時期PXR基因之表現---------------------------- 88
Figure 9B：斑馬魚仔魚時期PXR基因之表現---------------------------- 89
Figure 10：注射PXR及AHR2專一性MO對胚胎外形的影響------- 90
Figure 11：PXR-MO對斑馬魚CYP3A65基因表現之影響------------ 91
Figure 12：PXR-MO對斑馬魚CYP3C1基因表現之影響-------------- 92
Figure 13：AHR2-MO對斑馬魚CYP3A65基因表現之影響---------- 93
Figure 14：AHR2-MO對斑馬魚CYP3C1基因表現之影響------------ 94
Figure 15：AHR2-MO對斑馬魚PXR基因表現之影響----------------- 95
Figure 16：斑馬魚CYP3A65及CYP3C1基因的調控------------------ 96
柒、附錄----------------------------------------------------------------------- 97
附表一、各化合物之結構式與其簡介-------------------------------------- 97
附圖一：不同動物外生性毒化物感受細胞核受器之演化樹----------- 98
附圖二：AHR::ARNT訊息傳遞參與CYP3A65基因調控可能機制- 99
附錄一：Morpholino製造原理-------------------------------------- ---------100

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