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

我们之前的研究表明马钱子生物碱可以诱导CYP2B3，这是CYP2B亚家族的一个祖先形式。(Yamada et al.，生物医学杂志。, 19291 - 293, 1996)。这一观察结果表明，一种“动植物战争”的概念可能在CYP2B亚家族的进化中起作用，而CYP2B亚家族可以催化许多异种生物。本研究的目的之一是进一步探讨上述可能性，并将12种植物毒性成分给予大鼠进行诱导活性研究。结果表明，除可卡因外，所有化合物均对CYP2B亚家族包括CYP2B3具有诱导活性。而乌头碱、烟碱、茄碱等化合物对其他细胞色素家族P450 （P450）有一定的增加作用。这些观察结果表明，负责植物毒素的p450不仅分布在CYP2B中，还分布在其他家族中。马钱子生物碱相关化合物；即，ajmaline， pancuromium和gallamine诱导CYP2B3和CYP2B1/2。因此，很明显，诱导CYP2B3需要士的宁、马钱子碱和相关化合物的结构特征，而不是它们的毒性。另外进行了一个单独的实验来研究物种对CYP2B3诱导的差异。结果表明，马钱子碱在仓鼠、小鼠和豚鼠中没有引起CYP2B亚家族的任何诱导。然而，在这些动物中，马钱子碱处理增加了P450的其他亚家族。因此，我们发现先前报道的马钱子生物碱诱导的CYP2B亚家族祖先形式含量的增加是大鼠特异性的。该研究表明，如果“动植物战争”是P450酶进化的驱动力之一，那么不同家族的许多同工异构体将获得外源诱导。

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.