Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7
Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7
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DOI：
10.1124/dmd.30.8.883
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发表时间：
2002-08-01
影响因子：
3.9
通讯作者：
Wrighton, SA
中科院分区：
文献类型：
--
作者：
Williams, JA;Ring, BJ;Wrighton, SA
人细胞色素P450（P450）CYP 3A有助于50%的氧化代谢药物的生物转化。主要的肝脏形式是CYP 3A 4，但最近的证据表明，CYP 3A 5对总肝脏CYP 3A的贡献比最初认为的更显着。CYP 3A 7是主要的胎儿形式，在成人中很少表达。为了比较CYP 3A形式对10种底物的代谢能力，使用一致摩尔比（1：7：9）的重组CYP 3A、P450还原酶和细胞色素b5进行孵育。检查了广泛的底物浓度，以确定代谢产物形成动力学模型的最佳拟合。一般而言，CYP 3A 4底物的Km或S-50值比CYP 3A 5或CYP 3A 7低3 - 4倍。为了更直接地比较这些P450形式，将代谢物的清除率确定为所检查的最低底物浓度的代谢物形成速率的线性关系。在低底物浓度下，CYP 3A 4和CYP 3A 5对1 '-羟基咪达唑仑形成的清除率相似。对于CYP 3A 5与CYP 3A 4，其他生物转化在低底物浓度下的清除率值低2 - 20倍。在低底物浓度下，CYP 3A 7催化代谢产物形成的清除率值显著低于CYP 3A 4或CYP 3A 5，克拉霉素、4-OH三唑仑和N-去甲基地尔硫卓除外（CYP 3A 5与CYP 3A 7近似）。CYP 3A形式在某些生物转化中表现出区域选择性差异。这些结果表明，与CYP 3A 4相比，CYP 3A 5的代谢能力相等或降低，而CYP 3A 7的代谢能力显著降低。
The human cytochromes P450 (P450) CYP3A contribute to the biotransformation of 50% of oxidatively metabolized drugs. The predominant hepatic form is CYP3A4, but recent evidence indicates that CYP3A5 contributes more significantly to the total liver CYP3A than was originally thought. CYP3A7 is the major fetal form and is rarely expressed in adults. To compare the metabolic capabilities of CYP3A forms for 10 substrates, incubations were performed using a consistent molar ratio (1: 7: 9) of recombinant CYP3A, P450 reductase, and cytochrome b5. A wide range of substrate concentrations was examined to determine the best fit to kinetic models for metabolite formation. In general, K-m or S-50 values for the substrates were 3 to 4 times lower for CYP3A4 than for CYP3A5 or CYP3A7. For a more direct comparison of these P450 forms, clearance to the metabolites was determined as a linear relationship of rate of metabolite formation for the lowest substrate concentrations examined. The clearance for 1'-hydroxy midazolam formation at low substrate concentrations was similar for CYP3A4 and CYP3A5. For CYP3A5 versus CYP3A4, clearance values at low substrate concentrations were 2 to 20 times lower for the other biotransformations. The clearance values for CYP3A7-catalyzed metabolite formation at low substrate concentrations were substantially lower than for CYP3A4 or CYP3A5, except for clarithromycin, 4-OH triazolam, and N-desmethyl diltiazem (CYP3A5 approximate to CYP3A7). The CYP3A forms demonstrated regioselective differences in some of the biotransformations. These results demonstrate an equal or reduced metabolic capability for CYP3A5 compared with CYP3A4 and a significantly lower capability for CYP3A7.