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

新型CYP2B的功能及其诱导结构-诱导活性关系

• 批准号: 07672365
• 负责人: YAMADA Hideyuki
• 金额: $ 1.47万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672365/
• 关键词: Cytochrome P450; CYP2B subfamily; Strychnos alkaloid; Animal-plant warfare; Hamster; Guinea pig; Rat; Plant toxins; フェノベルビタール; 動物-植物闘争; フェノバビタール; 酵素誘導; 進化

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.

我们之前的研究表明，马钱子生物碱可诱导 CYP2B3（CYP2B 亚家族的祖先形式）。 (Yamada 等人，Biol.Pharm.Bull.，19，291-293，1996)。这一观察结果表明，“动植物战争”这一概念可能在 CYP2B 亚家族的进化中发挥作用，该亚家族可以催化许多外源物质。本研究的目的之一是进一步调查上述可能性，将植物中的 12 种有毒成分给予大鼠并检查其诱导活性。结果显示，除了可卡因之外，没有检测到的化合物对包括CYP2B3在内的CYP2B亚家族具有诱导活性。然而，一些化合物如乌头碱、尼古丁和龙葵碱稍微增加了其他家族的细胞色素P450（P450）。这些观察表明，负责植物毒素的 P450 不仅分布于 CYP2B，还分布于其他家族。马钱子生物碱相关化合物；即阿马林、泮库溴铵和没食子胺引起 CYP2B3 以及 CYP2B1/2 的诱导。因此，很明显，马钱子碱、马钱子碱和相关化合物中所见的结构特征，而不是它们的毒性对于诱导 CYP2B3 是必需的。进行了一项单独的实验来检查 CYP2B3 诱导的物种差异。结果，马钱子碱不会对仓鼠、小鼠和豚鼠的 CYP2B 亚家族产生任何诱导作用。然而，对这些动物进行马钱子碱治疗后，P450 的其他亚科的数量有所增加。因此，之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被发现对大鼠具有特异性。这项研究表明，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亚型将获得异生素诱导能力。