Structural requirements for the induction of hepatic microsomal cytochrome P450 by imidazole- and pyridine-containing compounds in rats.
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.
Kobayashi
Y
Y
Showa College of Pharmaceutical Sciences, Tokyo.
Matsuura
Y
Y
Kotani
E
E
Fukuda
T
T
Aoyagi
T
T
Tobinaga
S
S
Yoshida
T
T
Kuroiwa
Y
Y
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D007093:Imidazoles; D011725:Pyridines; D015082:2,2'-Dipyridyl; D003577:Cytochrome P-450 Enzyme System; D003022:Clotrimazole