1993 年 114 巻 5 号 p. 697-701
We investigated the structural requirements for the induction of hepatic microsomal cytochrome P 450 2B1/2 (P450 2B1/2) and cytochrome P 450 1A1/2 (P 450 1A1/2) by imidazole- and pyridine-containing compounds in rats. Clotrimazole, an azole antifungal drug, and 1-diphenylmethylimidazole preferentially induced P 450 2B1/2 in a dose-depen-dent manner, and slightly induced P 450 1A1/2. 1-Benzylimidazole preferentially induced P 450 1A1/2. 1-Phenylimidazole, which lacks the methylene bridge of 1-benzylimidazole, only induced P 450 1A1/2. In turn, loss of aromaticity of the N-substituted moiety of imidazole, as in 1-cyclohexylmethylimidazole and 1-tert-butylimidazole, resulted in a preferential induction of P450 2B1/2. Likewise, various pyridine-containing compounds showed structure-dependent induction of P 450 species. Namely, 4-diphenylmethyl-pyridine induced P 450 2B1/2.4-Benzylpyridine induced both P 450 2B1/2 and P 450 1A1/2. 4-Cyclohexylmethylpyridine and 4-tent-butylpyridine predominantly induced P 450 2B1/2.4-Phenylpyridine preferentially induced P 450 1A1/2 rather than P 450 2B1/2. Oxygenation products at the methylene bridge, 4-benzoylpyridine and phenyl-4-pyridylmethanol, could not induce P 450 1A1/2. In turn, 2, 4'-dipyridyl induced both P 450 2B1/2 and P 450 1A1/2, but not 2, 2'-dipyridyl. 4, 4'-Trimethylenedipyridine preferentially induced P 450 1A1/2 at very low doses. These findings indicate that imidazole- and pyridine-containing compounds having lipophilic groups are inducers of hepatic P 450, and that such compounds having aromatic groups and taking coplanar conformational structures are potent inducers of P 450 1A1/2.
