Inhibition of the Enzymatic Activity of Heme Oxygenases by Azole-Based Antifungal Drugs

• DOI: 10.1124/jpet.106.102699
• Publication Date: 2006-06-29T01:15:22Z
• Authors: Robert T. Kinobe; Ryan A. Dercho; Jason Z. Vlahakis; James F. Brien; Walter A. Szarek; Kanji Nakatsu
• Keywords: Azole

Ketoconazole (KTZ) and other azole antifungal agents are known to have a variety of actions beyond the inhibition sterol synthesis in fungi. These drugs share structural features with series novel heme oxygenase (HO) inhibitors designed our laboratory. Accordingly, we hypothesized that therapeutically used azole-based effective HO inhibitors. Using gas chromatography quantify carbon monoxide formation vitro vivo, shown azole-containing potent Terconazole, sulconazole, KTZ were most IC₅₀ values 0.41 ± 0.01, 1.1 0.4, 0.3 0.1 μM for rat spleen microsomal activity, respectively. Kinetic characterization revealed was noncompetitive inhibitor. In presence (2.5 10 μM), <i>K</i>_m both brain not altered; however, significant decrease catalytic capacity (<i>V</i>_max) observed (<i>P</i> &lt; 0.005). also found weakly inhibit nitric-oxide synthase an 177 2 but had no effect on enzymatic activity NADPH cytochrome P450 reductase. Because these within concentration range humans, it is possible may play role some pharmacological antimycotic drugs.