Inhibition of the enzymatic activity of heme oxygenases by azole-based antifungal drugs
Inhibition of the enzymatic activity of heme oxygenases by azole-based antifungal drugs
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DOI：
10.1124/jpet.106.102699
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Nakatsu, Kanji
中科院分区：
文献类型：
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作者：
Kinobe, Robert T.;Dercho, Ryan A.;Nakatsu, Kanji
酮康唑（KTZ）和其他唑类抗真菌剂已知具有多种作用，而不仅仅是抑制真菌中的甾醇合成。这些药物与我们实验室设计的一系列新型血红素加氧酶（HO）抑制剂具有共同的结构特征。因此，我们假设治疗上使用的唑类抗真菌药物是有效的HO抑制剂。使用气相色谱定量一氧化碳形成在体外和体内，我们已经表明，含唑类抗真菌药物是有效的HO抑制剂。特康唑、硫康唑和KTZ是最有效的药物，对大鼠脾微粒体HO活性的IC 50值分别为0.41 +/- 0.01、1.1 +/- 0.4和0.3 +/- 0.1 μ M。动力学研究表明，KTZ是一种非竞争性HO抑制剂。在KTZ（2.5和10 μ M）的存在下，大鼠脾和脑微粒体HO的Km值没有改变，但观察到催化能力（V-max）显著降低（P < 0.005）。还发现KTZ对一氧化氮合酶有微弱的抑制作用，IC 50为177 +/- 2 μ M，但对NADPH细胞色素P450还原酶的酶活性没有影响。由于这些药物在人体中观察到的浓度范围内有效，因此HO的抑制可能在这些抗霉菌药物的某些药理作用中发挥作用。
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 therapeutically used azole-based antifungal drugs are effective HO inhibitors. 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, sulconazole, and KTZ were the most potent drugs with IC50 values of 0.41 +/- 0.01, 1.1 +/- 0.4, and 0.3 +/- 0.1 mu 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 mu M), K-m values for both rat spleen and brain microsomal HO were not altered; however, a significant decrease in the catalytic capacity (V-max) was observed (P < 0.005). KTZ was also found to weakly inhibit nitric-oxide synthase with an IC50 of 177 +/- 2 mu M but had no effect on the enzymatic activity of NADPH cytochrome P450 reductase. Because these drugs were effective within the concentration range observed in humans, it is possible that inhibition of HO may play a role in some of the pharmacological actions of these antimycotic drugs.