Kobayashi Y, Matsuura Y, Kotani E, Fukuda T, Aoyagi T, Tobinaga S, Yoshida T, Kuroiwa Y
Showa College of Pharmaceutical Sciences, Tokyo.
J Biochem. 1993 Nov;114(5):697-701. doi: 10.1093/oxfordjournals.jbchem.a124239.
We investigated the structural requirements for the induction of hepatic microsomal cytochrome P450 2B1/2 (P450 2B1/2) and cytochrome P450 1A1/2 (P450 1A1/2) by imidazole- and pyridine-containing compounds in rats. Clotrimazole, an azole antifungal drug, and 1-diphenylmethylimidazole preferentially induced P450 2B1/2 in a dose-dependent manner, and slightly induced P450 1A1/2. 1-Benzylimidazole preferentially induced P450 1A1/2. 1-Phenylimidazole, which lacks the methylene bridge of 1-benzylimidazole, only induced P450 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 P450 species. Namely, 4-diphenylmethylpyridine induced P450 2B1/2. 4-Benzylpyridine induced both P450 2B1/2 and P450 1A1/2. 4-Cyclohexylmethylpyridine and 4-tert-butylpyridine predominantly induced P450 2B1/2. 4-Phenylpyridine preferentially induced P450 1A1/2 rather than P450 2B1/2. Oxygenation products at the methylene bridge, 4-benzoylpyridine and phenyl-4-pyridylmethanol, could not induce P450 1A1/2. In turn, 2,4'-dipyridyl induced both P450 2B1/2 and P450 1A1/2, but not 2,2'-dipyridyl. 4,4'-Trimethylenedipyridine preferentially induced P450 1A1/2 at very low doses. These findings indicate that imidazole- and pyridine-containing compounds having lipophilic groups are inducers of hepatic P450, and that such compounds having aromatic groups and taking coplanar conformational structures are potent inducers of P450 1A1/2.
我们研究了含咪唑和吡啶的化合物在大鼠体内诱导肝微粒体细胞色素P450 2B1/2（P450 2B1/2）和细胞色素P450 1A1/2（P450 1A1/2）的结构要求。克霉唑（一种唑类抗真菌药物）和1-二苯甲基咪唑以剂量依赖性方式优先诱导P450 2B1/2，并轻微诱导P450 1A1/2。1-苄基咪唑优先诱导P450 1A1/2。缺乏1-苄基咪唑亚甲基桥的1-苯基咪唑仅诱导P450 1A1/2。反过来，咪唑N-取代部分的芳香性丧失，如在1-环己基甲基咪唑和1-叔丁基咪唑中，导致优先诱导P450 2B1/2。同样，各种含吡啶的化合物对P450同工酶的诱导也表现出结构依赖性。具体而言，4-二苯甲基吡啶诱导P450 2B1/2。4-苄基吡啶诱导P450 2B1/2和P450 1A1/2。4-环己基甲基吡啶和4-叔丁基吡啶主要诱导P450 2B1/2。4-苯基吡啶优先诱导P450 1A1/2而非P450 2B1/2。亚甲基桥上的氧化产物4-苯甲酰吡啶和苯基-4-吡啶甲醇不能诱导P450 1A1/2。反过来，2,4'-联吡啶诱导P450 2B1/2和P450 1A1/2，但2,2'-联吡啶不能。4,4'-三亚甲基联吡啶在非常低的剂量下优先诱导P450 1A1/2。这些发现表明，具有亲脂性基团的含咪唑和吡啶的化合物是肝P450的诱导剂，并且具有芳香基团并采取共平面构象结构的此类化合物是P450 1A1/2的有效诱导剂。
