Induction of cytochrome P450 3A by paclitaxel in mice: Pivotal role of the nuclear xenobiotic receptor, pregnane X Receptor
Induction of cytochrome P450 3A by paclitaxel in mice: Pivotal role of the nuclear xenobiotic receptor, pregnane X Receptor
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DOI：
10.1124/dmd.31.5.681
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发表时间：
2003-05-01
影响因子：
3.9
通讯作者：
Desai, PB
中科院分区：
文献类型：
--
作者：
Nallani, SC;Goodwin, B;Desai, PB
紫杉醇是一种紫杉烷类抗微管药物，已知可诱导大鼠和人肝细胞中的CYP 3A。最近的研究表明，细胞核受体家族的一个成员，甾烷X受体（PXR），是不同物种中CYP 3A表达的关键调节因子。我们在体外和体内研究了PXR激活在紫杉醇介导Cyp 3a诱导中的作用。孕烯醇酮16 α-甲腈（PCN），一种抗糖皮质激素，被用作体外小鼠PXR（mPXR）激活和体内Cyp 3a诱导的阳性对照。在基于细胞的报告基因测定中，紫杉醇和PCN分别以5.6和0.27 μ M的EC 50激活mPXR。使用PXR野生型和缺乏功能性PXR（-/-）的转基因小鼠，我们评估了紫杉醇和PCN治疗后CYP 3A的表达和活性。在PXR野生型小鼠中，紫杉醇显著诱导CYP 3A 11 mRNA和免疫反应性CYP 3A蛋白。与CYP 3A诱导动力学一致，紫杉醇和PCN处理小鼠微粒体组分中睾酮6 β-羟基化的Vmax分别增加15倍和30倍。Cyp 3a诱导反应在紫杉醇和PCN处理的PXR-null小鼠中完全消除。这表明紫杉醇介导的体内CYP 3A诱导需要完整的PXR信号传导机制。我们的研究验证了使用PXR激活试验筛选新的紫杉烷类潜在的药物相互作用，可能与PXR靶基因诱导。
Paclitaxel, a taxane anti-microtubule agent, is known to induce CYP3A in rat and human hepatocytes. Recent studies suggest that a member of the nuclear receptor family, pregnane X Receptor (PXR), is a key regulator of the expression of CYP3A in different species. We investigated the role of PXR activation, in vitro and in vivo, in mediating Cyp3a induction by paclitaxel. Pregnenolone 16alpha-carbonitrile (PCN), an antiglucocorticoid, was employed as a positive control for mouse PXR ( mPXR) activation in vitro, and Cyp3a induction in vivo. In cell based reporter gene assays paclitaxel and PCN activated mPXR with an EC50 of 5.6 and 0.27 muM, respectively. Employing PXR wild-type and transgenic mice lacking functionalPXR(-/-), we evaluated the expression and activity of CYP3A following treatment with paclitaxel and PCN. Paclitaxel significantly induced CYP3A11 mRNA and immunoreactive CYP3A protein in PXR wild-type mice. Consistent with kinetics of CYP3A induction, the V-max of testosterone 6beta-hydroxylation in microsomal fraction increased 15- and 30-fold in paclitaxel- and PCN-treated mice, respectively. The Cyp3a induction response was completely abolished in paclitaxel- and PCN-treated PXR-null mice. This suggests that paclitaxel- mediated CYP3A induction in vivo requires an intact PXR-signaling mechanism. Our study validates the use of PXR activation assays in screening newer taxanes for potential drug interactions that may be related to PXR-target gene induction.