Cytochrome P-450是生物轉化作用(biotransformation) phase 1中對藥物、毒素和內生性物質進行氧化最主要的代謝酵素之一，負責代謝大約50%的臨床用藥，其中多數的藥物具有首渡代謝(first-pass effect)的情形。臨床研究發現性別之間存在著藥物動力學的差異；先前本實驗室的研究也顯示CYP3A5基因多型性對於不同劑型的鈣離子阻斷劑-nifedipine在藥物動力學的影響上是存在著性別及腸道部位的差異。相對於人類的CYP3A4、3A5，在大鼠則是表現CYP3A1、3A2。我們希望透過in vivo的實驗觀察Sprague-Dawley大鼠肝臟和腸道各個部位CYP3A1和CYP3A2蛋白質在不同年齡、性別的表現量變化，以釐清性別差異與其中是否有腸道代償性表現CYP3A的情形。
初步結果顯示隨著年齡的增加CYP3A1在肝臟的表現量會下降，而在腸道則會上升，CYP3A1在肝臟的表現量比小腸多2-10倍；CYP3A2只在大鼠的肝臟表現，但成熟雌性大鼠則幾乎不表現。整體而言雄性大鼠CYP3A蛋白表現量比雌性大鼠多，有報導指出可能是個體為了調節生理狀況，例如:維持荷爾蒙代謝的恆定，進而影響CYP3A的表現量，但詳細的分子機制目前仍不清楚。
為了進一步探討雄性荷爾蒙是否參與調控CYP3A，我們利用藥物和手術的方式將雄性大鼠去勢，發現去勢的雄性大鼠其肝臟CYP3A1和CYP3A2的表現量明顯減少；給予雄性荷爾蒙補充療法以後，可使兩者的表現量回復。而給予雌性大鼠testosterone後也發現肝臟CYP3A1和CYP3A2都有顯著的增加，顯示雄性荷爾蒙的濃度與肝臟CYP3A1和CYP3A2的表現量之間有密切的關係。綜合以上的實驗証實CYP3A的表現量會受到性別、年齡以及荷爾蒙的影響，但並未發現腸道代償性表現CYP3A的情形。
關鍵字:雄性荷爾蒙；細胞色素3A1；細胞色素3A2

Cytochrome P450 monooxygenases (CYPs) is a superfamily of hemoproteins responsible for the biotransformation of many exogenous and endogenous chemicals. Our laboratory
previously reported that the influence of CYP3A5 expression on the pharmacokinetics is associated with gender and the location of small intestine. However the mechanisms involved in this physiological regulation have not yet been characterized. Human expresses two major cytochrome P450 isoforms, CYP3A4 and CYP3A5 that are oligomerically related to rats CYP3A1 and CYP3A2. In order to clarify whether the gender-related differences in the hepatic and intestinal expression of CYP3As are present, we have characterized expression of CYP3A1 protein and CYP3A2 protein in hepatocytes and small intestinal enterocytes of rat. The preliminary results showed age-associated decline in liver CYP3A1 expression in both sexs, whereas it increased in intestine. CYP3A1 is much higher in the liver than in the duodenum, jejunum and ileum. CYP3A2 was expressed in liver in 10-day in both sexs. However, the levels decreased over time and disappeared in female at 10 weeks of age. CYP3A2 was undetectable in intestine in either male or female at any age. Male rats expressed more CYP3As protein than females. Recent studies have implicated hormone regulates sex-dependent CYP450s through the interaction of the hormone-receptor complex with gene cis-acting elements. To further investigate the effect of testosterone on the expression of CYP3As, we used androgen ablation therapy by chemical or surgical castration. Androgen ablation therapy led to significantly reduction in the CYP3A1 and CYP3A2 in liver. The alternations can be reversed by testosterone replacement. Taken together, these results suggest complex gender-, tissue- and development-specific patterns which are controlled by hormones of the CYP 3As expression.
Key word: testosterone; CYP3A1; CYP3A2

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