Wiśniewska Anita, Chrapkowska Agnieszka, Kot-Wasik Agata, Konopa Jerzy, Mazerska Zofia
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland.
Acta Biochim Pol. 2007;54(4):831-8. Epub 2007 Dec 17.
The imidazoacridinone derivative C-1311 is an antitumor agent in Phase II clinical trials. The molecular mechanism of enzymatic oxidation of this compound in a peroxidase model system was reported earlier. The present studies were performed to elucidate the role of rat and human liver enzymes in metabolic transformations of this drug. C-1311 was incubated with different fractions of liver cells and the reaction mixtures were analyzed by RP-HPLC. We showed that the drug was more sensitive to metabolism with microsomes than with cytosol or S9 fraction of rat liver cells. Incubation of C-1311 with microsomes revealed the presence of four metabolites. Their structures were identified as dealkylation product, M0, as well as a dimer-like molecule, M1. Furthermore, we speculate that the hydroxyl group was most likely substituted in metabolite M3. It is of note that a higher rate of transformation was observed for rat than for human microsomes. However, the differences in metabolite amounts were specific for each metabolite. The reactivity of C-1311 with rat microsomes overexpressing P450 isoenzymes, of CYP3A and CYP4A families was higher than that with CYP1A and CYP2B. Moreover, the M1 metabolite was selectively formed with CYP3A, whereas M3 with CYP4A. In conclusion, this study revealed that C-1311 varied in susceptibility to metabolic transformation in rat and human cells and showed selectivity in the metabolism with P450 isoenzymes. The obtained results could be useful for preparing the schedule of individual directed therapy with C-1311 in future patients.
咪唑并吖啶酮衍生物C-1311是一种正处于II期临床试验阶段的抗肿瘤药物。此前已报道了该化合物在过氧化物酶模型系统中酶促氧化的分子机制。本研究旨在阐明大鼠和人肝脏酶在该药物代谢转化中的作用。将C-1311与肝细胞的不同组分一起孵育，并用反相高效液相色谱法分析反应混合物。我们发现，该药物对大鼠肝细胞微粒体代谢的敏感性高于对胞质溶胶或S9组分的敏感性。C-1311与微粒体孵育后显示存在四种代谢产物。它们的结构被鉴定为脱烷基产物M0以及一种二聚体样分子M1。此外，我们推测代谢产物M3中的羟基最有可能被取代。值得注意的是，观察到大鼠微粒体的转化速率高于人微粒体。然而，每种代谢产物的量的差异是特定的。C-1311与过表达CYP3A和CYP4A家族P450同工酶的大鼠微粒体的反应性高于与CYP1A和CYP2B的反应性。此外，M1代谢产物是由CYP3A选择性形成的，而M3是由CYP4A形成的。总之，本研究表明C-1311在大鼠和人细胞中对代谢转化的敏感性不同，并且在与P450同工酶的代谢中表现出选择性。所获得的结果可能有助于为未来患者制定C-1311个体化定向治疗方案。
