The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China.
Acta Pharmacol Sin. 2009 Oct;30(10):1462-70. doi: 10.1038/aps.2009.127. Epub 2009 Sep 21.
To characterize the metabolism of cardamonin by the P450 enzymes in human and animal liver microsomes.
Cardamonin was incubated with both human and animal liver microsomal incubation systems containing P450 reaction factors. High performance liquid chromatography coupled with ion trap mass spectrometry was used to identify the metabolites. Serial cardamonin dilutions were used to perform a kinetic study in human liver microsomes. Selective inhibitors of 7 of the major P450 isozymes were used to inhibit cardamonin hydroxylation to identify the isozymes involved in cardamonin metabolism. The cardamonin hydroxylation metabolic capacities of human and various other animals were investigated using the liver microsomal incubation system.
Two metabolites generated by the liver microsome system were detected and identified as hydroxylated cardamonin. The Km and Vmax values for cardamonin hydroxylation were calculated as 32 micromol/L and 35 pmol x min(-1) x mg(-1), respectively. Furafylline and clomethiazole significantly inhibited cardamonin hydroxylation. Guinea pigs showed the highest similarity to humans with respect to the metabolism of cardamonin.
CYP 1A2 and 2E1 were identified as the P450 isozymes involved in the metabolism of cardamonin in human liver microsomes. Furthermore, our research suggests that guinea pigs could be used in the advanced pharmacokinetic studies of cardamonin in vivo.
研究卡达明在人及动物肝微粒体中的 P450 酶代谢特征。
卡达明与人及动物肝微粒体孵育系统中包含 P450 反应因子孵育，用高效液相色谱-离子阱质谱联用技术鉴定其代谢产物。用卡达明的系列稀释液在人肝微粒体中进行动力学研究。用 7 种主要 P450 同工酶的选择性抑制剂抑制卡达明羟化作用，以鉴定参与卡达明代谢的同工酶。用肝微粒体孵育系统研究卡达明在人及其他动物肝微粒体中的羟化代谢能力。
在肝微粒体系统中检测到并鉴定出两种生成的代谢产物为羟化卡达明。卡达明羟化的 Km 和 Vmax 值分别为 32 μmol/L 和 35 pmol·min-1·mg-1。呋喃氟拉嗪和氯米扎酮能显著抑制卡达明羟化作用。豚鼠在代谢卡达明方面与人最为相似。
CYP1A2 和 2E1 被鉴定为人肝微粒体中卡达明代谢的 P450 同工酶。此外，我们的研究表明豚鼠可用于卡达明体内药代动力学的深入研究。
