Matsuura Y, Kotani E, Iio T, Fukuda T, Tobinaga S, Yoshida T, Kuroiwa Y
Showa College of Pharmaceutical Sciences, Tokyo, Japan.
Biochem Pharmacol. 1991 Jun 15;41(12):1949-56. doi: 10.1016/0006-2952(91)90135-r.
We investigated the structure-activity relationship in the induction of hepatic microsomal cytochrome P450 by clotrimazole and its structurally related compounds. For this purpose, we synthesized various compounds structurally analogous to clotrimazole and injected them into rats at a fixed dose of 0.2 mmol/kg. We found that the chlorine atom in clotrimazole was not necessary for the induction of cytochrome P450. The imidazole moiety of clotrimazole, however, was a very important structural component for the induction of cytochrome P450; triazole, but not pyrrole, could be substituted for this moiety. 1-Tritylimidazole, 1-diphenylmethylimidazole and 1-benzylimidazole were also found to be inducers of cytochrome P450, but, to a somewhat lesser extent, with a decreasing number of substituted phenyl groups. Thus, 1-benzylimidazole was a minimum structurally active unit for inducing cytochrome P450. In addition, 4-diphenylmethylpyridine and 4-benzylpyridine also induced cytochrome P450 to extents similar to those induced by the corresponding imidazole derivatives, but 4-benzylpiperidine lacked this effect. When the methylene unit of clotrimazole-related compounds was introduced by a hydroxy or amino group instead of imidazole, there was a less extensive increase in cytochrome P450 content. This inducing effect was lost completely by the lack of an imidazole moiety and imidazole itself. 1-Phenylethylimidazole and 1-benzylimidazole induced cytochrome P450 to a similar extent. All of these findings suggest that 1-substituted heteroaromatic compounds having two or more nitrogen atoms are likely to be required for inducing cytochrome P450. Immunoblot analysis revealed that clotrimazole and other various inducers found in this study increased cytochrome P450b/e content. These results could provide information on the effects of drugs and chemicals on cytochrome P450 induction.
我们研究了克霉唑及其结构相关化合物诱导肝微粒体细胞色素P450的构效关系。为此，我们合成了各种与克霉唑结构类似的化合物，并以0.2 mmol/kg的固定剂量注射到大鼠体内。我们发现，克霉唑中的氯原子对于细胞色素P450的诱导并非必需。然而，克霉唑的咪唑部分是诱导细胞色素P450的非常重要的结构成分；三唑而非吡咯可以替代该部分。1-三苯甲基咪唑、1-二苯甲基咪唑和1-苄基咪唑也被发现是细胞色素P450的诱导剂，但程度稍低，随着取代苯基数量的减少而降低。因此，1-苄基咪唑是诱导细胞色素P450的最小结构活性单元。此外，4-二苯甲基吡啶和4-苄基吡啶也能诱导细胞色素P450，其程度与相应的咪唑衍生物诱导的程度相似，但4-苄基哌啶没有这种作用。当克霉唑相关化合物的亚甲基单元被羟基或氨基而非咪唑引入时，细胞色素P450含量的增加幅度较小。由于缺乏咪唑部分和咪唑本身，这种诱导作用完全丧失。1-苯乙基咪唑和1-苄基咪唑诱导细胞色素P450的程度相似。所有这些发现表明，具有两个或更多氮原子的1-取代杂芳族化合物可能是诱导细胞色素P450所必需的。免疫印迹分析显示，克霉唑和本研究中发现的其他各种诱导剂增加了细胞色素P450b/e的含量。这些结果可以提供有关药物和化学物质对细胞色素P450诱导作用的信息。
