Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites
Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites
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DOI：
10.1016/j.bcp.2012.04.001
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发表时间：
2012-07-15
影响因子：
5.8
通讯作者：
Murray, Michael
中科院分区：
文献类型：
--
作者：
Ghassabian, Sussan;Rawling, Tristan;Murray, Michael
酪氨酸激酶抑制剂药物索拉非尼用于治疗肝癌和肾癌，但不良反应可能需要剂量中断，剂量不足可能导致治疗失败。索拉非尼还经历细胞色素P450(CYP)依赖的生物转化为N-氧化物和其他代谢物。然而，尽管细胞色素P450是疗效和毒性的主要决定因素，但这些酶在形成多个索拉非尼代谢产物中的作用尚不清楚。在本研究中，我们评估了CYP介导的索拉非尼在人肝脏中的氧化途径。基因表达的CYP3A4是索拉非尼主要N-氧化物和N-羟甲基代谢物以及次要N-脱甲基代谢物形成的主要催化剂。相比之下，CYP3A5的活性仅为CYP3A4的5%，其他11个CYP和3个含有黄素的单加氧酶处于失活状态。在人肝微粒体中，代谢产物的形成与CYP3A4介导的咪达唑仑1‘-羟化有关，但与其他CYP特异性底物氧化无关。与这些发现一致的是，细胞色素P3A4抑制剂酮康唑选择性地抑制了微粒体索拉非尼的氧化途径。从计算模型研究中，索拉非尼结构中经过生物转化的原子与CyP3A4血红素的5.4埃相似。索拉非尼与CYP3A4活性中心的氨基酸Ser-119和Glu-374之间存在重要的氢键相互作用。这些发现表明索拉非尼被人的细胞色素P3A4选择性氧化。这些信息可以用个性化的方法进行调整，以优化索拉非尼在癌症患者中的安全性和有效性。(C)2012 Elsevier Inc.保留所有权利。
The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under-dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites. However, although CYPs are major determinants of efficacy and toxicity the roles of these enzymes in the formation of multiple sorafenib metabolites are unclear. In the present study CYP-mediated pathways of sorafenib oxidation in human liver were evaluated. cDNA-expressed CYP3A4 was the major catalyst in the formation of the principal N-oxide and N-hydroxymethyl metabolites of sorafenib, as well as the minor N-desmethyl metabolite. In contrast, CYP3A5 exhibited only similar to 5% of the activity of CYP3A4 and eleven other CYPs and three Flavin-containing monooxygenases were inactive. In human hepatic microsomes metabolite formation was correlated with CYP3A4-mediated midazolam 1'-hydroxylation, but not with other CYP-specific substrate oxidations. In accord with these findings the CYP3A4 inhibitor ketoconazole selectively inhibited microsomal sorafenib oxidation pathways. From computational modeling studies atoms in the structure of sorafenib that undergo biotransformation were within similar to 5.4 angstrom of the CYP3A4 heme. Important hydrogen bonding interactions between sorafenib and amino acids Ser-119 and Glu-374 in the active center of CYP3A4 were identified. These findings indicate that sorafenib is oxidized selectively by human CYP3A4. This information could be adapted in individualized approaches to optimize sorafenib safety and efficacy in cancer patients. (C) 2012 Elsevier Inc. All rights reserved.