Department of Pharmacology and Toxicology, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, USA.
Chem Res Toxicol. 2010 Aug 16;23(8):1356-64. doi: 10.1021/tx100124k.
Inhaled glucocorticoid (GC) therapy is a vital part of the management of chronic asthma. GCs are metabolized by members of the cytochrome P450 3A family in both liver and lung, but the enzymes are differentially expressed. Selective inhibition of one or more P450 3A enzymes could substantially modify target and systemic concentrations of GCs. In this study, we have evaluated the mechanism-based inactivation of P450 3A4, 3A5, and 3A7 enzymes by GCs. Among the five major inhaled GCs approved for clinical use in the United States, fluticasone propionate (FLT) was the most potent mechanism-based inactivator of P450 3A5, the predominant P450 enzyme in the lung. FLT inactivated P450 3A5 in a time- and concentration-dependent manner with K(I), k(inact), and partition ratio of 16 muM, 0.027 min(-1), and 3, respectively. In contrast, FLT minimally inactivated P450 3A4 and did not inactivate 3A7, even with a concentration of 100 muM. The inactivation of P450 3A5 by FLT was irreversible because dialysis did not restore enzyme activity. In addition, the exogenous nucleophilic scavenger GSH did not attenuate inactivation. The prosthetic heme of P450 3A5 was not modified by FLT. The loss of P450 3A5 activity in lung cells could substantially decrease the metabolism of FLT, which would increase the effective FLT concentration at its target site, the respiratory epithelium. Also, inactivation of lung P450 3A5 could increase the absorption of inhaled FLT, which could lead to high systemic concentrations and adverse effects, such as life-threatening adrenal crises or cataracts that have been documented in children receiving high doses of inhaled GCs.
吸入性糖皮质激素（GC）治疗是慢性哮喘管理的重要组成部分。GC 在肝脏和肺部均由细胞色素 P450 3A 家族成员代谢，但这些酶的表达存在差异。对一种或多种 P450 3A 酶的选择性抑制可能会显著改变 GC 的靶位和全身浓度。在这项研究中，我们评估了 GC 对 P450 3A4、3A5 和 3A7 酶的基于机制的失活作用。在美国批准用于临床使用的五种主要吸入性 GC 中，丙酸氟替卡松（FLT）是肺中主要 P450 酶 P450 3A5 的最强效基于机制的失活剂。FLT 以时间和浓度依赖的方式失活 P450 3A5，K(i)、k(inact)和分配比分别为 16 μM、0.027 min(-1)和 3。相比之下，FLT 对 P450 3A4 的失活作用很小，即使浓度达到 100 μM，也不会失活 3A7。FLT 对 P450 3A5 的失活作用是不可逆的，因为透析不能恢复酶活性。此外，外源性亲核试剂 GSH 不能减弱失活作用。FLT 未修饰 P450 3A5 的辅基血红素。肺细胞中 P450 3A5 活性的丧失可显著降低 FLT 的代谢，从而增加其靶位（呼吸道上皮）的有效 FLT 浓度。此外，肺 P450 3A5 的失活可增加吸入性 FLT 的吸收，从而导致全身浓度升高和不良反应，例如在接受高剂量吸入性 GC 的儿童中已记录到的危及生命的肾上腺危象或白内障。
