Bu H-Z
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Curr Drug Metab. 2006 Apr;7(3):231-49. doi: 10.2174/138920006776359329.
Cytochrome P450 (CYP) enzymes represent a superfamily of hemoproteins that are involved in the metabolism of a wide variety of endogenous and exogenous compounds. For a given CYP enzyme, kinetic properties of a substrate are usually related to substrate lipophilicity (log P or log D(7.4)). In this review, enzyme kinetic parameters (K(m), V(max), and V(max)/K(m)) of 215 CYP3A4-mediated metabolic reactions of 113 drugs in human liver microsomes were obtained from the literature, and lipophilicity values of the 113 drugs were calculated using the ACD/Labs 8.0 program. A low degree of K(m)- or (V(max)/K(m))-lipophilicity correlation, but no V(max)-lipophilicity correlation, is exhibited for the CYP3A4-mediated reactions. Overall, K(m) decreases, but V(max)/K(m) increases, with increasing substrate lipophilicity, and V(max) appears to be independent of substrate lipophilicity. In other words, a low K(m) generally confers a high V(max)/K(m) ratio for a substrate. The degree of lipophilicity-kinetics correlations is related to both reaction types (or reaction mechanisms) and regiochemical positions (or physicochemical properties) of the reaction groups of the substrates. Among the categorized CYP3A4-mediated reactions, the best lipophilicity-kinetics correlation is achieved for carbon hydroxylation, followed by N-dealkylation. No or little lipophilicity-kinetics correlations are seen for N, S-oxidation and other reactions. Within the hydroxylation group, aliphatic hydroxylation shows the best lipophilicity-kinetics correlation while hydroxylation on a carbon atom adjacent to an aromatic ring does not show any lipophilicity-kinetics correlation. The detailed structural and kinetic data sets of the human liver microsomal CYP3A4-mediated reactions represent a specialized database useful for researchers working in the area of structure-metabolism relationship modeling and analysis.
细胞色素P450（CYP）酶是一类血红蛋白超家族，参与多种内源性和外源性化合物的代谢。对于特定的CYP酶，底物的动力学性质通常与底物亲脂性（log P或log D(7.4)）相关。在本综述中，从文献中获取了113种药物在人肝微粒体中215个CYP3A4介导的代谢反应的酶动力学参数（K(m)、V(max)和V(max)/K(m)），并使用ACD/Labs 8.0程序计算了这113种药物的亲脂性值。CYP3A4介导的反应显示出K(m)或（V(max)/K(m)）与亲脂性的低程度相关性，但没有V(max)与亲脂性的相关性。总体而言，随着底物亲脂性的增加，K(m)降低，但V(max)/K(m)增加，并且V(max)似乎与底物亲脂性无关。换句话说，低K(m)通常赋予底物高V(max)/K(m)比值。亲脂性与动力学的相关程度与反应类型（或反应机制）以及底物反应基团的区域化学位置（或物理化学性质）有关。在分类的CYP3A4介导的反应中，碳羟基化反应的亲脂性与动力学相关性最佳，其次是N-脱烷基化反应。对于N、S-氧化和其他反应，未观察到或仅有很少的亲脂性与动力学相关性。在羟基化组中，脂肪族羟基化显示出最佳的亲脂性与动力学相关性，而芳环相邻碳原子上的羟基化未显示出任何亲脂性与动力学相关性。人肝微粒体CYP3A4介导反应的详细结构和动力学数据集代表了一个专门的数据库，对从事结构-代谢关系建模和分析领域的研究人员很有用。
