臺灣博碩士論文加值系統

土震素 (territrem)為土麴菌編號23-1 (Aspergillus terreus 23-1)菌株經米培養後所產生的黴菌毒素，以氯仿萃取分離成土震素A、B、C (TRA、TRB、TRC)三種震顫性毒素。本實驗室先前的研究得知，土震素A經成熟雄性大鼠肝臟微粒體代謝，先由水解作用 (hydroxylation)產生MA1，其次經氧化作用 (oxidation)產生MAX，最後經脫酸作用 (decarbonylation)產生MA2，而成熟之雌性大鼠肝臟微粒體對土震素A的代謝僅能行水解作用產生MA1，而無法再氧化及脫酸作用產生MAX及MA2。探討何種細胞色素P450參與土震素A之代謝，得知CYP3A1及CYP3A2參與MA1的產生，而CYP3A2參與MAX及MA2的產生。因而更進一步要了解雄性及雌性大鼠肝臟微粒體中細胞色素P450 3A1及3A2之蛋白及mRNA之表現差異性及關連於土震素的代謝是否也有性別的差異。
諸多的研究中得知，老化改變許多外來毒性物質包括藥物的代謝能力，與體內參與代謝酵素P450之改變有關聯。因此想了解，參與土震素A代謝過程之CYP3A1及CYP3A2是否也會因老化的現象而有所改變以及與性荷爾蒙調控之相關性。
研究結果得知以下結果：(1)雄性與雌性大鼠2-76週大期間CYP3A1蛋白及mRNA持續的表現。 (2)2-52週大的雄性大鼠CYP3A2蛋白及mRNA持續的表現，但於76週大之後即開始下降，而於雌性大鼠中CYP3A2的蛋白及mRNA表現，於6週大後極速降低。(3)CYP3A1及CYP3A2的表現，雄性大鼠高於雌性大鼠。 (4)土震素的代謝因其芳香基上結構的差異，產生不同的代謝產物。 (5) 52週大後之雄性大鼠MAX及MA2下降，且在雌性大鼠於6週大後即無MAX與MA2的生成。 (6)雄性大鼠TRB之代謝產物MB2產量大於雌性大鼠，而TRC的代謝產物MB1則雌性大鼠大於雄性大鼠。 (7) 雄性大鼠性腺摘除後處理高劑量testosterone 750 mg可回復CYP3A2蛋白含量及MAX及MA2的生成。
綜合以上的研究結果，我們證實 (1)土震素A之代謝具有性別的差異，主要是與CYP3A2蛋白及mRNA表現有關；土震素A、B及C因結構的不同經代謝後有不同的代謝產物。另外76週的雄性大鼠CYP3A1/2的蛋白、mRNA表現及對土震素代謝的能力都下降，表示老化改變雄性大鼠酵素表現及代謝能力，傾向於女性化的情形。 (2) CYP3A2之表現可受testosterone性荷爾蒙的調控，而造成性別上代謝能力的不同，老化後體內的testosterone濃度降低，而改變肝臟微粒體對土震素的代謝。由此推斷，土震素代謝具性別及年齡的差異主要是因CYP3A2表現之改變，而這樣的改變與男性荷爾蒙的調控有關。

Three tremogenic mycotoxines, designated as territrem A, B and C (TRA, TRB and TRC) were isolated from a chloroform extract of rice culture of Aspergillus terreus 23-1.The metabolism of TRA in liver microsomes of adult male and female rats have been studied. Three metabolites of TRA were formed by three sequential oxidative steps in male rats. There are first, hydroxylation at the 4b-C methyl group of TRA to form MA1; second, oxidation at 4b-C hydroxyl group of MA1 to form MAX; and third, decarbonylation at the 4b-C oxo group of MAX to form MA2. However, in female only MA1 was formed from TRA. Further, studies of cytochrome P450 isforms catalyzing TRA metabolism revealed that MA1 formation is catalyzed by both CYP3A1 and CYP3A2, while the formation of MAX and MA2 are catalyzed by CYP3A2. The sex difference of both amounts of protein and mRNA of CYP3A1/2 expression and territrems metabolism were examined in the present study.
Many studies concerning age-related changes in CYP450 linked to metabolism of xenobiotics and drug have been reported. Therefore, next study of CYP3A1 and CYP3A2 related to age and sex hormone are our major concern.
In the present studies, the following results were obtained: (1)Both protein and mRNA of CYP3A1 are constitutively expressed in both gender at 2- to 76-week-old age. (2)The protein levels and mRNA of CYP3A2 constitutively expressed in 2- to 52-week-old male rats, but they decreased after 76-week-old age, and decreased in female rat when after 6-week-old. (3)The expression of CYP3A1 or CYP3A2 in male rats are generally higher than female rats. (4)Formation of the different metabolites was due to change of aromatic moiety of territrems. (5)Formation of MAX and MA2 decreased after 52-week-old male rats and ceased after 6-week-old female rats. (6)The amount of MB2 formed in female rats was less than in male rats, but the amount of MB1 (TRC metabolites) formed in female rats was higher than male rats. (7)The protein levels of CYP3A2, production of MAX and MA2 were restored by administration on high dose testosterone (750 mg) in the castrated male rats.
Therefore, it is concluded that: (1) The metabolism of TRA have sexual difference were related to the protein and mRNA expression of CYP3A2. The different metabolites formed could be due to the modification of the chemical structure of the aromatic moiety of territrems. The protein levels and mRNA expression of CYP3A2 and efficiency of territrems metabolism were decreased after 76-week-old that cause feminization at elder age of male rats. (2)Testosterone status modulated CYP3A2 expression and caused sex differenced of metabolism. For instances, serum level of testosterone decreased after aging and then changed territrems metabolism efficiency. In conclusion, age- and gender-related changes on territrems metabolism were due to CYP3A2 expression which regulated by testosterone.

目 錄
中文摘要……………………………………………………………….. .I
英文摘要………………………………………………………………..III
目錄……………………………………………………………………....V
表目錄……………………………………………………………….…..VI
圖目錄……………………………………………………………….….VII
縮寫表…………………………………………………………………....X
第一章 不同年齡及性別大鼠肝臟微粒體中之細胞色素P450之表現及
testosterone之代謝作用……………………………………1
第二章 大鼠肝臟微粒體中細胞色素P450對土震素A之代謝及分
析………………………………………………………………36
第三章 大鼠肝臟微粒體中細胞色素P450對土震素B及土震素C之代謝及
分析……………………………………………………......51
第四章 土震素A在大鼠肝臟微粒體中之代謝與荷爾蒙調節之相關探
討………………………….………………………….………64
第五章 總結……………………………………………………………83
第六章 參考文獻………………………………………………………90
附圖、表

第六章 參考文獻
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