SELECTIVITY OF ISOPRENOID-CONTAINING IMIDAZOLE ANTIFUNGAL COMPOUNDS FOR STEROL 14-DEMETHYLASE P450 (P450(14DM)) AND 7-ETHOXYCOUMARIN O-DEETHYLASE P450 OF RAT-LIVER MICROSOMES

被引：0

作者：

ITO, T ^{[1
]}

AOYAMA, Y ^{[1
]}

ISHIDA, K ^{[1
]}

KUDOH, M ^{[1
]}

HORI, K ^{[1
]}

TSUCHIYA, S ^{[1
]}

YOSHIDA, Y ^{[1
]}

机构：

[1] MUKOGAWA WOMENS UNIV,FAC PHARMACEUT SCI,NISHINOMIYA,HYOGO 663,JAPAN

来源：

BIOCHEMICAL PHARMACOLOGY | 1994年 / 48卷 / 08期

关键词：

CYTOCHROME P450; ANTIFUNGAL AGENT; STEROL DEMETHYLASE INHIBITOR; TARGET SELECTIVITY; STEROL DEMETHYLASE; RAT LIVER;

D O I：

暂无

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The imidazole antifungal compound AFK-108 (1-[2-(2,4-dichlorophenyl)-2-((2E)-3,7-dimethylocta-2,6-dienyloxy)ethyl]-1H-imidazole) has been shown to be a potent inhibitor for yeast lanosterol 14 alpha-demethylase (P450(14DM)), interacting specifically with the sterol side-chain recognition part of the substrate site through its geranyl moiety. AFK-108 acted as a potent inhibitor for rat liver P450(14DM), while its farnesyl (AFK-110) and prenyl (AFK-122) homologues were weak inhibitors. This indicates that AFK-108 interacts with rat liver P450(14DM) in the same manner as with the yeast enzyme. However, the difference between the potency of AFK-108 and the homologues was greater in rat P450(14DM) than in the yeast enzyme. AFK-108 and its homologues partially inhibited 7-ethoxycoumarin O-deethylase activity of rat liver microsomes. The order of potency was AFK-122 > AFK-108 > AFK-110, indicating that some steric hindrance of the isoprenoid moiety might affect their potency. The inhibitory effect of AFK-108 for P450(14DM) was considerably higher than for 7-ethoxycoumarin O-deethylase P450, while the inhibition of AFK-110 and AFK-122 on these enzymes was of the same order of magnitude. These results suggest that azole compounds interacting with the side-chain recognition site of P450(14D)M may be good candidates as antifungal agents selective for fungal P450(14D)M

引用

页码：1577 / 1582

页数：6