Malathion detoxification by human hepatic carboxylesterases and its inhibition by isomalathion and other pesticides
Malathion detoxification by human hepatic carboxylesterases and its inhibition by isomalathion and other pesticides
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DOI：
10.1002/jbt.20106
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发表时间：
2005-01-01
影响因子：
3.6
通讯作者：
Testai, E
中科院分区：
文献类型：
--
作者：
Buratti, FM;Testai, E
哺乳动物体内的有机硫代磷酸酯（OPT）农药马拉硫磷（MAL）容易被哺乳动物羧酸酯酶（CE）水解。该反应与CYP催化的毒性代谢物马劳酮（MOX）的形成竞争。CE活性的改变或个体差异可能导致MOX形成增加，从而增强MAL毒性。我们已经表征了一组18个人肝微粒体中的人肝CE活性以及IsoMAL（MAL商业制剂的主要杂质）、敌百虫磷（PAR）、毒死蜱（CPF）和毒死蜱-氧磷（CPFO）的抑制作用。CE活性在个体之间表现出低水平的变化（4倍）。反应由两个不同的相组成，其对MAL的亲和力不同（K-m1 = 0.25-0.69 μ M; K-m2 = 10.3-26.8 μ M）。相对较低的K-m1值证实，人CE有效地解毒MAL. IsoMAL被证明是一个有效的非竞争性抑制剂MAL解毒（Ki = 0.6 μ M），具有更高的抑制效力比CPF和PAR（Ki = 7.5 μ M和50 μ M，分别）。后两种化合物很可能充当混合抑制剂。CPFO对CE介导的解毒显示出最高的抑制效力，其特征在于Ki = 22 nM。目前的结果提供了有用的信息，更好地了解不同的OPT之间可能的相互作用，并为评估潜在的累积风险暴露于OPT混合物。(c)2005 Wiley Periodicals，Inc.
The organophosphorothioate (OPT) pesticide malathion (MAL) in mammals is readily hydrolyzed by mammalian carboxylesterases (CE). The reaction competes with the CYP-catalyzed formation of malaoxon (MOX), the toxic metabolite. Alterations or individual variations in CE activity may result in increased MOX formation, enhancing MAL toxicity. We have characterized the human hepatic CE activity in a panel of 18 human liver microsomes as well as the inhibitory effect of IsoMAL, a major impurity of MAL commercial formulations, parathion (PAR), chlorpyrifos (CPF), and chlorpyrifos-oxon (CPFO). CE activity showed a low level of variation among individuals (4-fold). The reaction consists of two different phases, differing in their affinity for MAL (K-m1 = 0.25-0.69 mu M; K-m2 = 10.3-26.8 mu M). The relatively low K-m1 values confirmed that human CE efficiently detoxify MAL. IsoMAL was shown to be a potent noncompetitive inhibitor of MAL detoxification (K-i = 0.6 mu M), with a higher inhibitory potency than CPF and PAR (K-i = 7.5 mu M and 50 mu M, respectively). These two latter compounds very likely act as mixed inhibitors. CPFO showed the highest inhibitory potency toward CE-mediated detoxification, being characterized by a K-i = 22 nM. The present results provide useful information for a better understanding of possible interactions between different OPTs and for assessing the potential cumulative risk for exposure to OPT mixtures. (c) 2005 Wiley Periodicals, Inc.