Biotransformation of methyl parathion by glutathione S-transferases
Biotransformation of methyl parathion by glutathione S-transferases
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DOI：
10.1093/toxsci/kfh118
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发表时间：
2004-06-01
影响因子：
3.8
通讯作者：
Eaton, DL
中科院分区：
文献类型：
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作者：
Abel, EL;Bammler, TK;Eaton, DL
有机（硫代）磷酸酯是最广泛使用的杀虫剂类别之一。在世界范围内，有机磷杀虫剂 (OP) 每年都会导致大量中毒事件。在昆虫中，谷胱甘肽 S-转移酶 (GST) 在 OP 抗性中发挥着重要作用。有限的数据表明 GST 介导的 O-脱烷基化也发生在人类身上。为了表征哺乳动物 GST 解毒 OP 的能力，我们研究了广泛使用的 OP 甲基对硫磷 (MeP) 的哺乳动物 GST 生物转化。从大鼠、小鼠和十个成人肝脏中分离的胞质级分分别以 2.36、1.76 和 0.70（平均速率）nmol 去甲基对硫磷/分钟/毫克的速率生物转化 300 muM MeP。我们的研究重点是人类商品及服务税；特别是，我们研究了 hGST M1-1 和 T1-1，因为缺失多态性通常发生在这些基因中。然而，我们发现十个人肝胞质样品的 hGSTM1/T1 基因型与 MeP O 脱烷基化活性之间没有相关性。我们还测量了几种纯化重组 GST 的 MePO O 脱烷基化活性，这些 GST 属于 α（人 GST A1-1 和 A2-2、小鼠 GSTA3-3、大鼠 GSTA5-5）、mu（人 GST M1a-1a、M2-2、M3-3、M4-4）、pi（人 GSTP1-1、小鼠 GST P1-1、P2-2）和 theta（人 GST） GSTT1-1) 类。在 1 mM 谷胱甘肽和 300 muM MeP 浓度下，hGSTT1-1 和 hGSTA1-1 表现出最高的 O-脱烷基化活性：分别为 545.8 和 65.0 nmol/min/mg。当考虑表达水平和酶活性时，我们估计 hGSTA1-1 负责人肝细胞质中大部分 MeP O-脱烷基化。在大脑和骨骼肌等 hGSTT1-1 表达的靶器官中，hGSTT1-1 介导的 MeP 生物转化可能很重要。
The organo(thio)phosphate esters are one of the most widely used classes of insecticides. Worldwide, organophosphate insecticides (OPs) result in numerous poisonings each year. In insects, glutathione S-transferases (GSTs) play an important role in OP resistance; limited data suggest that GST-mediated O-dealkylation occurs in humans as well. To characterize the capacity of mammalian GSTs to detoxify OPs, we investigated mammalian GST biotransformation of the widely used OP, methyl parathion (MeP). Cytosolic fractions isolated from rat, mouse, and ten individual adult human livers biotransformed 300 muM MeP at rates of 2.36, 1.76, and 0.70 (mean rate) nmol desmethyl parathion/min/mg, respectively. Our study focused on human GSTs; in particular, we investigated hGSTs M1-1 and T1-1, since deletion polymorphisms occur commonly in these genes. However, we found no correlation between hGSTM1/T1 genotypes and MeP O-dealkylation activities of the ten human liver cytosolic samples. We also measured MeP O-dealkylation activities of several purified recombinant GSTs belonging to the alpha (human GSTs A1-1 and A2-2, mouse GSTA3-3, rat GSTA5-5), mu (human GSTs M1a-1a, M2-2, M3-3, M4-4), pi (human GSTP1-1, mouse GSTs P1-1, P2-2), and theta (human GSTT1-1) classes. At 1 mM glutathione and 300 muM MeP concentrations, hGSTT1-1 and hGSTA1-1 exhibited the highest O-dealkylation activities: 545.8 and 65.0 nmol/min/mg, respectively. When expression level and enzymatic activity are considered, we estimate that hGSTA1-1 is responsible for the majority of MeP O-dealkylation in human hepatic cytosol. In target organs such as brain and skeletal muscle, where hGSTT1-1 is expressed, hGSTT1-1-mediated biotransformation of MeP may be important.