The relative contribution of human cytochrome P450 isoforms to the four caffeine oxidation pathways:: An in vitro comparative study with cDNA-expressed P450s including CYP2C isoforms
The relative contribution of human cytochrome P450 isoforms to the four caffeine oxidation pathways:: An in vitro comparative study with cDNA-expressed P450s including CYP2C isoforms
复制标题
DOI：
10.1016/j.bcp.2008.05.025
复制
发表时间：
2008-08-15
影响因子：
5.8
通讯作者：
Daniel, Wladyslawa A.
中科院分区：
文献类型：
--
作者：
Kot, Marta;Daniel, Wladyslawa A.
本研究的目的是估计细胞色素P450异构体（P450），包括P450的CYP 2C亚家族，在人类肝脏中的咖啡因代谢的相对贡献。在体外使用cDNA表达的P450、肝微粒体和特异性P450抑制剂进行实验。结果表明：（1）咖啡因除3-N-去甲基化-CYP 1A 2标记反应和咖啡因氧化途径中的主要氧化途径外，1-N-去甲基化也被CYP 1A 2特异性催化（此前未报道）;（2）7-N-去甲基化是非特异性催化的，主要由CYP 1A 2催化，在较小程度上由CYP 2C 8/9和CYP 3A 4催化（而不是CYP 2 E1，如前所述）;（3）C-8-羟基化优先涉及CYP 1A 2和CYP 3A 4，在较小程度上，涉及CYP 2C 8/9和CYP 2 E1（而不仅仅是CYP 3A，如前所述），浓度为100 μ M，对应于人体的最大治疗浓度。在较高的咖啡因浓度下，CYP 1A 2对该反应的贡献降低，有利于CYP 2C 8/9。所获得的数据首次显示了CYP 2C异构体对人肝脏中咖啡因代谢的贡献，并表明除了3-N-去甲基化外，1-N-去甲基化也可用于检测CYP 1A 2活性。此外，它们表明C-8-羟基化并非仅由CYP 3A 4催化。(C)2008年爱思唯尔公司All rights reserved.
The aim of the present study was to estimate the relative contribution of cytochrome P450 isoforms (P450s), including P450s of the CYP2C subfamily, to the metabolism of caffeine in human liver. The experiments were carried out in vitro using cDNA-expressed P450s, liver microsomes and specific P450 inhibitors. The obtained results show that (1) apart from the 3-N-demethylation of caffeine - a CYP1A2 marker reaction and the main oxidation pathway of caffeine in man - 1-N-demethylation is also specifically catalyzed by CYP1A2 (not reported previously); (2) 7-N-demethylation is catalyzed non-specifically, mainly by CYP1A2 and, to a smaller extent, by CYP2C8/9 and CYP3A4 (and not by CYP2E1, as suggested previously); (3) C-8-hydroxylation preferentially involves CYP1A2 and CYP3A4 and, to a smaller degree, CYP2C8/9 and CYP2E1 (and not only CYP3A, as suggested previously) at a concentration of 100 mu M corresponding to the maximum therapeutic concentration in humans. At a higher caffeine concentration, the contribution of CYP1A2 to this reaction decreases in favour of CYP2C8/9. The obtained data show for the first time the contribution of CYP2C isoforims to the metabolism of caffeine in human liver and suggest that apart from 3-N-demethylation, 1-N-demethylation may also be used for testing CYP1A2 activity. Moreover, they indicate that the C-8-hydroxylation is not exclusively catalyzed by CYP3A4. (C) 2008 Elsevier Inc. All rights reserved.