Function of a new form of CYP2B and the inducer structure-inducing activity relationship

我们前期的研究表明马钱子生物碱对CYP 2B亚家族的一个祖先型CYP 2B 3有诱导作用。（Yamada等人，生物医药部，19，291 - 293，1996）。这一观察结果表明，“动植物战争”概念可能在CYP 2B亚家族的进化中发挥作用，该亚家族可以催化许多外源性物质。本研究的目的之一是进一步探讨上述可能性，并将植物中的12种有毒成分给予大鼠，检测其诱导活性。结果表明，除可卡因外，所检测的化合物均不具有对包括CYP 2B 3在内的CYP 2B亚家族的诱导活性。而乌头碱、烟碱、龙葵碱等化合物对细胞色素P450的其它家族有一定的促进作用。这些观察结果表明，负责植物毒素的P450不仅分布于CYP 2B，而且还分布于其他家族。马钱子苷相关化合物;即，阿曲库铵、全铜和没食子酸引起CYP 2B 3和CYP 2B 1/2的诱导。因此，很明显，在士的宁、马钱子碱和相关化合物中观察到的结构特征，而不是它们的毒性，是诱导CYP 2B 3所必需的。进行了一项单独的实验，以检查对CYP 2B 3诱导的种属差异。结果表明，马钱子碱对仓鼠、小鼠和豚鼠的CYP 2B亚家族没有任何诱导作用。然而，在这些动物中，通过马钱子碱治疗，P450的其他亚家族增加。因此，马钱子碱诱导的CYP 2B亚家族的祖先形式的含量增加被认为是特定的大鼠。本研究表明，如果“动植物战争”是P450酶进化的驱动力之一，那么不同家族中的许多异构体都会受到外源物的诱导。

Our previous study indicated that strychnos alkaloid induces CYP2B3, an ancestral form of CYP2B subfamily. (Yamada et al., Biol.Pharm.Bull., 19,291-293,1996). This observation suggests a possibility that a concept "animal-plant wartfare" plays a role in the evolution of the CYP2B subfamily which can catalyze a number of xenobiotics. One of the objectives of this study was further investigation of above possibility, and twelve toxic ingredients in plants were given to rats and their inducing activity was examined. The results showed that no compounds examined except for cocaine have inducing activity toward CYP2B subfamily including CYP2B3. However, some compounds such as aconitine, nicotine and solanine a little increased other families of cytochrome P450 (P450). These observations suggest that the P450s responsible for plant toxins distribute to not only CYP2B but also other families. Strychnos alkaloid-related compounds ; i.e., ajmaline, pancuromium and gallamine caused the induction of CYP2B3 as well as CYP2B1/2. It is, therefore, evident that structural characteristics seen in strychnine, brucine and related compounds, but not their toxicity is needed for the induction of CYP2B3. A separate experiment was performed to examine species difference on the induction of CYP2B3. As the results, brucine did not cause any induction of the CYP2B subfamily in hamsters, mice and guinea pigs. Other subfamilies of P450 was, however, increased by brucine treatment in these animals. Therefore, the strychnos alkjaloid-induced increase in the content of ancestral form of CYP2B subfamily reported previously was found to be specific for rats. This study suggested that if "animal-plant warfare" is one of the driving forces in the evolution of P450 enzyme, many isoforms in different families would gain xenobiotics-inducibility.