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Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib

机译:拉帕替尼对人细胞色素P450 3A4的代谢中间体复合物的形成

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摘要

Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib.
机译:拉帕替尼,一种口服乳腺癌药物,最近被报道是一种基于机制的细胞色素P450(P450)3A4失活剂,也是一种特异的肝毒性药物。有人认为,反应性醌亚胺代谢物的形成与基于机制的失活(MBI)和/或肝毒性有关。我们研究了拉帕替尼对P450 3A4 MBI的作用机理。与拉帕替尼一起孵育后,P450 3A4的液相色谱-质谱分析未显示对应于不可逆修饰的任何峰。拉帕替尼灭活的酶活性通过添加铁氰化钾而完全恢复。这些结果表明拉帕替尼MBI的机制是准不可逆的,并且是通过代谢中间复合物(MI复合物)的形成介导的。大约455 nm处标志性Soret吸光度的增加证实了这一发现。表征了P450 3A4代谢拉帕替尼的两种胺氧化产物:N-羟基拉帕替尼(M3)和N-去烷基拉帕替尼的肟形式(M2),表明MI涉及亚硝基或其他相关中间体复杂的形成。相比之下,与P450 3A4相比,拉帕替尼通过MI复合物形成对P450 3A5的MBI敏感性要低得多。此外,P450 3A5生成M3的能力明显低于3A4,这与N-羟基化作为MI复合物形成途径的起始步骤相一致。总之,我们的结果表明,拉帕替尼对P450 3A4的MBI的主要机制不是醌亚胺代谢物的不可逆修饰,而是通过拉帕替尼的仲胺基氧化而介导的准不可逆MI复合物的形成。

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