Selectivity of isoprenoid-containing imidazole antifungal compounds for sterol 14-demethylase P450 (P450(14)DM) and 7-ethoxycoumarin O-deethylase P450 of rat liver microsomes.
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(14)DM), 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(14)DM, while its farnesyl (AFK-110) and prenyl (AFK-122) homologues were weak inhibitors. This indicates that AFK-108 interacts with rat liver P450(14(DM 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(14)DM 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(14)DM 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(14)DM may be good candidates as antifungal agents selective for fungal P450(14)DM.
Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
T
T
Ito
Y
Y
Aoyama
K
K
Ishida
M
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Kudoh
K
K
Hori
S
S
Tsuchiya
Y
Y
Yoshida
D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D058886:Sterol 14-Demethylase
D000935:Antifungal Agents; C548417:Cyp51 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; C078434:AFK 108; D010088:Oxidoreductases; D015660:7-Alkoxycoumarin O-Dealkylase; D058886:Sterol 14-Demethylase; D007654:Ketoconazole