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

Ketoconazole (KTZ) and other azole antifungal agents are known to have a variety of actions beyond the inhibition of sterol synthesis in fungi. These drugs share structural features with a series of novel heme oxygenase (HO) inhibitors designed in our laboratory. Accordingly, we hypothesized that therapeuti-cally used azole-based antifungal drugs are effective HO inhibi-tors. Using gas chromatography to quantify carbon monoxide formation in vitro and in vivo, we have shown that azole-containing antifungal drugs are potent HO inhibitors. Terconazole, sulcon-azole, and KTZ were the most potent drugs with IC50 values of 0.41 0.01, 1.1 0.4, and 0.3 0.1 M for rat spleen microsomal HO activity, respectively. Kinetic characterization revealed that KTZ was a noncompetitive HO inhibitor. In the presence of KTZ (2.5 and 10 M), Km values for both rat splee