Usia Tepy, Watabe Tadashi, Kadota Shigetoshi, Tezuka Yasuhiro
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Japan.
Biol Pharm Bull. 2005 Jun;28(6):1021-4. doi: 10.1248/bpb.28.1021.
The MeOH-soluble fraction of the water extract of Catharanthus roseus from Indonesia, having shown potent inhibitory activity on the metabolism mediated by CYP2D6, was subjected to activity-guided isolation to yield two triterpenes, ursolic acid (1) and oleanolic acid (2), and three alkaloids, vindoline (3), ajmalicine (4), and serpentine (5). The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-14C]erythromycin or [O-methyl-14C]dextromethorphan as a substrate, respectively. Ajmalicine (4) and serpentine (5) showed very potent inhibitory activity against CYP2D6 with IC50 values of 0.0023 and 3.51 microM, respectively. All isolated compounds showed weak or no inhibition against CYP3A4. On time-, concentration-, and NADPH-dependent assay, serpentine (5) appear to be the mechanism-based inhibitor for CYP2D6 enzyme in which the inhibition was irreversible and driven by catalytic process. K(I) and k(inact) values for serpentine (5) were 0.148 microM and 0.090 min-1, respectively. On the other hand, ajmalicine (4) showed no time-dependent inhibition or reversible inhibition, and thus appear to be not mechanism-based inhibitor.
来自印度尼西亚的长春花水提取物的甲醇可溶部分，已显示出对CYP2D6介导的代谢具有强大的抑制活性，对其进行活性导向分离，得到两种三萜类化合物，熊果酸（1）和齐墩果酸（2），以及三种生物碱，长春多灵（3）、阿吗碱（4）和蛇根碱（5）。分别使用[N-甲基-14C]红霉素或[O-甲基-14C]右美沙芬作为底物，测试分离出的化合物对CYP3A4或CYP2D6介导的代谢的抑制活性。阿吗碱（4）和蛇根碱（5）对CYP2D6表现出非常强大的抑制活性，IC50值分别为0.0023和3.51 microM。所有分离出的化合物对CYP3A4均表现出微弱抑制或无抑制作用。在时间、浓度和NADPH依赖性试验中，蛇根碱（5）似乎是CYP2D6酶的基于机制的抑制剂，其抑制作用是不可逆的且由催化过程驱动。蛇根碱（5）的K（I）和k（inact）值分别为0.148 microM和0.090 min-1。另一方面，阿吗碱（4）未表现出时间依赖性抑制或可逆抑制，因此似乎不是基于机制的抑制剂。
