The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 enzyme.
The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 enzyme.
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DOI：
10.1021/tx100124k
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发表时间：
2010-08-16
影响因子：
4.1
通讯作者：
Yost, Garold S.
中科院分区：
文献类型：
--
作者：
Murai, Takahiro;Reilly, Christopher A.;Ward, Robert M.;Yost, Garold S.
吸入糖皮质激素(GC)治疗是慢性哮喘治疗的重要组成部分。GCS在肝脏和肺中均由细胞色素P450 3A家族成员代谢，但酶的表达存在差异。选择性地抑制一个或多个P450 3A酶可以显著改变GCs的靶浓度和全身浓度。在这项研究中，我们评估了GCs对P450 3A4、3A5和3A7酶的失活机制。在美国批准临床使用的五种主要吸入性GC中，丙酸氟替卡松(flticasone propiate，Flt)是肺中主要的P450酶P450 3A5最有效的基于机制的灭活剂。Flt以时间和浓度依赖的方式灭活P4503A5，其Ki值、活度和分配比分别为16min M、0.027μ-1和3。相反，Flt对P450 3A4的失活作用最小，即使在100μM的浓度下也不能使3A7失活。由于透析不能恢复酶的活性，Flt对P450 3A5的失活是不可逆的。此外，外源性亲核清除剂GSH不能减弱灭活作用。P450 3A5的人工血红素未被Flt修饰。肺细胞P4503A5活性的丧失可显著降低Flt的代谢，从而增加其靶部位呼吸道上皮的有效Flt浓度。此外，肺P450 3A5的失活可能会增加吸入性Flt的吸收，这可能导致高系统浓度和不良反应，如已记录的在接受大剂量吸入GCs的儿童中危及生命的肾上腺危象或白内障。
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 KI, kinact and partition ratio of 16 μM, 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 μM. 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.
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