7,8-Dehydrorutaecarpione 及其甲氧基衍生物對細胞色素P450 1 之抑制作用   全文下載

Inhibition of CYP1 by 7,8-Dehydrorutaecarpine and Its Methoxylated Derivatives

7,8-dehydrorutaecarpine 是細胞色素P450（CYP）1a1 與1a2 之強抑制物，加入甲氧基會減弱其對CYP1a1 之抑制作用，因而相對地提高其對CYP1a2 或CYP1b1 之選擇性抑制作用。衍生物中，以2-methoxy-7,8-dehydrorutaecarpine 對CYP1a2 具最佳之選擇性抑制作用；然而，加入4- 甲氧基會使其抑制CYP1b1 之iC50 值降低，使其對CYP1b1 具最佳之選擇性抑制作用。分子模擬的結果顯示2-methoxy-7,8-dehydrorutaecarpine 上之2-甲氧基與CYP1a2 之Thr113 可形成氫健。2-Methoxy-7,8-dehydrorutaecarpine是CYP1a2 之noncompetitive 與 uncompetitive 抑制物， 其對CYP1a2與CYP1a2- 受質結合物之抑制參數分別為9.5 ± 2.6 與6.7 ± 2.6 nM。對7,8-dehydrorutaecarpine 及rutaecarpine 之2- 甲氧基衍生物而言，將其2- 甲氧基改為2- 乙氧基會降低其抑制CYP1a1 之iC50 值，但升高抑制CYP1a2之iC50 值。我們的結果證實將alkoxy 基加入7,8-dehydrorutaecarpine 的結構中，可影響其抑制CYP1 ?之選擇性。這些結果可提供了解CYP1 與以7,8-dehydrorutaecarpine 為中心結構之抑制物間作用之重要依據。"

7,8-Dehydrorutaecarpine was a potent inhibitor of both CYP1A1 and CYP1A2. The introduction of methoxyl group reduced CYP1A1 inhibition and enhanced the relative inhibition selectivity to either CYP1A2 or CYP1B1. Among the synthesized derivatives, 2-methoxy-7,8-dehydrorutaecarpine had the best selectivity of CYP1A2 inhibition. In contrast, the introduction of 4-methoxyl group decreased the IC50 values for CYP1B1 and had the best selectivity of CYP1B1 inhibition. Results of molecular modeling showed that a hydrogen bond was formed between the 2-methoxyl group of 2-methoxy-7,8-dehydrorutaecarpine and Thr113 residue of CYP1A2. 2-Methoxy-7,8-dehydrorutaecarpine was a mixed type inhibitor of CYP1A2 with the inhibition constants of 9.5 ± 2.6 and 6.7 ± 2.6 nM for CYP1A2 and CYP1A2-substrate complex, respectively. For the 2- methoxyl derivatives of 7,8-dehydrorutaecarpine and rutaecarpine, the change of 2-methoxyl to an 2-ethoxyl group decreased and increased the IC50 values for CYP1A1 and CYP1A2, respectively. Our results demonstrated that introduction of alkoxyl modification to a heterocyclic compound, 7,8-dehydrorutaecarpine could change inhibitory selectivity among CYP1 enzymes. These results may provide important information for the interaction between CYP1 members and their inhibitors with a core structure of 7,8-dehydrorutaecarpine.