| 摘要: | 細胞色素 P450 (P450, CYP) 1族扮演一個很重要的角色對於解毒與活化不同的外來物質(如藥物、致癌物、殺蟲劑)與人體內生化合物(如類固醇)。CYP 1的亞族包含了三個成員(CYP1A1、CYP1A2與CYP1B1)被發現於人體內。藥物代謝中氧化與結合反應是兩個主要的過程。藥物在CYP 酵素上的調控作用是造成藥物交互作用的主要原因之一。
先前研究報告指出，由吳茱萸所分離出來的rutaecarpine在老鼠及人類肝臟微粒體顯示很強的選擇及抑制CYP1A2的活性。進一步引進methoxyl group在rutaecarpine結構上的不同位置發現對CYP1成員有不同程度的活性表現。在這些rutaecarpine衍生物中，10- 與11-methoxyrutaecarpine具有很高的選擇性抑制CYP1B1酵素。1-Methoxyrutaecarpine具有很高的選擇性抑制CYP1A2酵素。除此之外，7,8-dehydrorutaecarpine具有很高的抑制CYP1的活性但無選擇性。
將methoxyl group置入rutaecarpine的適當位置或在7,8位置上改變為雙鍵對於CYP1各成員的抑制活性與選擇性是很重要的。在此論文中，一系列有甲氧基取代的7,8-dehydrorutaecarpine被合成出來，其中7,8-dehydro-10-methoxyrutaecarpine具有選擇性抑制CYP1A2酵素的活性。
Cytochrome P450 (P450, CYP) 1 family plays an important role in detoxication and activation of various xenobiotics (e.g., drugs, carcinogens, and pesticides) and endogenous compounds (e.g., steroids).
The CYP1 subfamily including three members (CYP1A1, CYP1A2, and CYP1B1) are identified in human. Oxidation and conjugation are two main reaction involved in drug metabolism. Modulatory effect of drug on CYP enzymes is one of the main causes of drug interaction.
In our previous studies, rutaecarpine isolated from Evodia rutaecarpa was a selective and potent inhibitor of CYP1A2 in both mouse and human liver microsomes. Introduction of a methoxyl group at various position of rutaecarpine was evaluated the inhibitory effects on CYP1 enzymes. Among the derivatives of rutaecarpine, 10- and 11-methoxyrutaecarpine were the most selective CYP1B1 inhibitors. 1-Methoxyrutaecarpine was the most selective CYP1A2 inhibitor. In addition, 7,8-dehydrorutaecarpine was a potent CYP1 inhibitor without obvious selectivity between CYP1 members.
The positions of methoxyl group or 7,8-double bond of rutaecarpine are important in determining the inhibitory potency and selectivity. In this thesis, a series of methoxylated 7,8-dehydrorutaecarpines were synthesized, and their inhibitory effects on CYP1 members were also evaluated. The result showed that 7,8-dehydro-10-methoxyrutaecarpine shifted the CYP1 inhibition from non-selective to CYP1A2-selective inhibition. |
