STRUCTURAL REQUIREMENTS FOR THE INDUCTION OF HEPATIC-MICROSOMAL CYTOCHROME-P450 BY IMIDAZOLE-CONTAINING AND PYRIDINE-CONTAINING COMPOUNDS IN RATS

被引：26

作者：

KOBAYASHI, Y ^{[1
]}

MATSUURA, Y ^{[1
]}

KOTANI, E ^{[1
]}

FUKUDA, T ^{[1
]}

AOYAGI, T ^{[1
]}

TOBINAGA, S ^{[1
]}

YOSHIDA, T ^{[1
]}

KUROIWA, Y ^{[1
]}

机构：

[1] SHOWA UNIV,SCH PHARMACEUT SCI,DEPT BIOCHEM TOXICOL,SHINAGAWA KU,TOKYO,TOKYO 142,JAPAN

来源：

JOURNAL OF BIOCHEMISTRY | 1993年 / 114卷 / 05期

关键词：

D O I：

10.1093/oxfordjournals.jbchem.a124239

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：697 / 701

页数：5