细胞色素P450的工具药选择及种属差异的研究进展

药物对代谢酶的影响以及代谢产生的药物相互作用与药物安全性密切相关。细胞色素P450(CYP)是参与内、外源性化合物I相代谢反应的重要超家族酶系。特异性探针、诱导剂、抑制剂以及实验动物模型广泛应用于CYP介导的代谢途径以及药物相互作用研究。已知CYP底物存在明显重叠性,且表达调控机制种属差异显著,故研究中选择适当的实验动物以及特异性的探针、诱导剂和抑制剂,成为影响数据外推的关键问题。本文简要综述了CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP3A4/5的常用体内外探针、诱导剂、抑制剂以及动物种属表达调控的差异。

Progress in selection of tool drugs and species differences of cytochrome P450

The regulation of drug-metabolizing enzymes by drugs and drug-drug interactions via these enzymes are closely related to the safety of drugs. Cytochrome P450 (CYP) is an important superfamily of mono-oxygenases which are responsible for phaseⅠ metabolism of most endobiotics and xenobiotics. Specific probes, inducers and inhibitors, as well as experimental animal models are widely used in the studies on metabolism pathways via CYP, the regulation of CYP by drugs and DDI. It is well known that the substrates of CYP are overlapping, and that the pattern of the expression and regulation of CYP by drugs is different across species. Therefore, the selection of an appropriate animal model, specific probe, inducer and inhibitor during preclinical studies is the determinant of data extrapolation from animals to humans. As CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 are the major isoforms responsible for the biotransformation of clinically used drugs, we briefly reviewed the specificity of the commonly used in vivo and in vitro probes, inducers, inhibitors as well as the difference in the expression and regulation of these isoforms between species.