Metabolism of styrene in the human liver in vitro:: interindividual variation and enantioselectivity
Metabolism of styrene in the human liver in vitro:: interindividual variation and enantioselectivity
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DOI：
10.1080/00498250010031638
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发表时间：
2001-02-01
期刊：
影响因子：
1.8
通讯作者：
De Wolff, FA
中科院分区：
文献类型：
--
作者：
Wenker, MAM;Kezic, S;De Wolff, FA
1.本文研究了20个人肝微粒体中细胞色素P450体外氧化苯乙烯反应的个体差异和对映体选择性。对肝脏样本进行CYP 2 E1 *6和CYP 2 E1 * 5 B等位基因的基因分型。动力学分析表明，存在至少两种形式的苯乙烯代谢细胞色素P450。高亲和力组分的酶常数存在明显的个体间差异，即V-max 1范围为0.39 - 3.20 nmol mg蛋白（-1）min（-1）（0.96 +/- 0.63），K-m1范围为0.005 - 0。03 mM（0.011 +/- 0.006）。使用CYP 2 E1、CYP 1A 2、CYP 2C 8/9和CYP 3A 4的化学抑制剂进行的抑制研究表明，CYP 2 E1是参与苯乙烯氧化的高亲和力组分的主要酶。V-max 1和K-m1的个体间变异与CYP 2 E1基因多态性无关.细胞色素P450介导的苯乙烯氧化表现出中等的对映体选择性，在低苯乙烯浓度下（S）-氧化苯乙烯的对映体过量（ee）为15%（范围4-27%），在高苯乙烯浓度下（R）-氧化苯乙烯的ee为7%（范围-11至+22%）。这指向参与至少两个细胞色素P450，具有不同的对映体选择性。4.这些数据表明，细胞色素P450介导的苯乙烯氧化受到相当大的个体间的变化，但只有一个温和的产品对映选择性。
1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles.2. Kinetic analysis indicated the presence of at least two forms of styrene-metabolizing cytochrome P450. The enzyme constants for the high-affinity component were subject to appreciable interindividual variation, i.e. V-max1 ranged from 0.39 to 3.20 nmol mg protein(-1) min(-1) (0.96 +/- 0.63) and K-m1 ranged from 0.005 to 0. 03 mM (0.011 +/- 0.006). Inhibition studies with chemical inhibitors of CYP2E1, CYP1A2, CYP2C8/9 and CYP3A4 demonstrated that CYP2E1 was the primary enzyme involved in the high-affinity component of styrene oxidation. No relationship between the interindividual variation in V-max1 and K-m1 and the genetic polymorphisms of the CYP2E1 gene was found.3. Cytochrome P450-mediated oxidation of styrene demonstrated a moderate enantioselectivity, with an enantiomeric excess (ee) of (S)-styrene oxide of 15% (range 4-27%) at low styrene concentration and an ee of (R)-styrene oxide of 7% (range -11 to +22%) at high styrene concentration. This points towards the involvement of at least two cytochrome P450, with different enantioselectivities.4. The data indicate that cytochrome P450-mediated styrene oxidation is subject to considerable interindividual variation, but only to a moderate product enantioselectivity.