Ross Matthew K, Borazjani Abdolsamad, Edwards Carol C, Potter Philip M
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, PO Box 6100 Mississippi State, MS 39762-6100, USA.
Biochem Pharmacol. 2006 Feb 28;71(5):657-69. doi: 10.1016/j.bcp.2005.11.020. Epub 2006 Jan 4.
Pyrethroid chemicals are attractive alternatives to the organophosphates (OPs) because of their selective toxicity against pests rather than mammals. The carboxylesterases (CEs) are hepatic enzymes that metabolize ester-containing xenobiotics such as pyrethroids. The primary aim of this study was to gain insight into the catalytic properties of the CE enzymes in humans that metabolize pyrethroids, while a secondary aim was to investigate pyrethroid metabolism using CEs from other mammalian species. Pure human CEs (hCE-1 and hCE-2), a rabbit CE (rCE), and two rat CEs (Hydrolases A and B) were used to study the hydrolytic metabolism of the following pyrethroids: 1Rtrans-resmethrin (bioresmethrin), 1RStrans-permethrin, and 1RScis-permethrin. hCE-1 and hCE-2 hydrolyzed trans-permethrin 8- and 28-fold more efficiently than cis-permethrin (when k(cat)/K(m) values were compared), respectively. In contrast, hydrolysis of bioresmethrin was catalyzed efficiently by hCE-1, but not by hCE-2. The kinetic parameters for the pure rat and rabbit CEs were qualitatively similar to the human CEs when hydrolysis rates of the investigated pyrethroids were evaluated. Further, a comparison of pyrethroid hydrolysis by hepatic microsomes from rats, mice, and humans indicated that the rates for each compound were similar between species, which further supports the use of rodent models for pyrethroid metabolism studies. An eight-fold range in hydrolytic rates for 11 individual human liver samples toward trans-permethrin was also found, although this variability was not related to the levels of hCE-1 protein in each sample. We also determined that the CE inhibitor 2-chloro-3,4-dimethoxybenzil blocked hCE-2-catalyzed trans-permethrin hydrolysis 36 times more potently than hCE-1. Thus, this inhibitor will be useful in future studies that examine CE-mediated metabolism of pyrethroids. While there are likely other esterases in human liver that hydrolyze pyrethroids, the results of this study clearly demonstrate that hCE-1 and hCE-2 are human pyrethroid-hydrolyzing CEs.
拟除虫菊酯类化学物质是有机磷酸酯类（OPs）颇具吸引力的替代品，因为它们对害虫具有选择性毒性，而非对哺乳动物。羧酸酯酶（CEs）是一种肝脏酶，可代谢含酯类的外源性物质，如拟除虫菊酯。本研究的主要目的是深入了解人体中代谢拟除虫菊酯的CE酶的催化特性，次要目的是利用其他哺乳动物物种的CEs研究拟除虫菊酯的代谢。使用纯人类CEs（hCE - 1和hCE - 2）、兔CE（rCE）以及两种大鼠CEs（水解酶A和B）来研究以下拟除虫菊酯的水解代谢：1R反式 - 苄呋菊酯（生物苄呋菊酯）、1RS反式 - 氯菊酯和1RS顺式 - 氯菊酯。当比较k(cat)/K(m)值时，hCE - 1和hCE - 2水解反式氯菊酯的效率分别比顺式氯菊酯高8倍和28倍。相比之下，hCE - 1能有效催化生物苄呋菊酯的水解，而hCE - 2则不能。当评估所研究拟除虫菊酯的水解速率时，纯大鼠和兔CEs的动力学参数在性质上与人类CEs相似。此外，对大鼠、小鼠和人类肝脏微粒体对拟除虫菊酯水解的比较表明，各物种对每种化合物的水解速率相似，这进一步支持了使用啮齿动物模型进行拟除虫菊酯代谢研究。还发现11个个体人类肝脏样本对反式氯菊酯的水解速率有八倍的差异范围，尽管这种变异性与每个样本中hCE - 1蛋白的水平无关。我们还确定，CE抑制剂2 - 氯 - 3,4 - 二甲氧基苯甲酰阻断hCE - 2催化的反式氯菊酯水解的效力比hCE - 1高36倍。因此，这种抑制剂将有助于未来研究拟除虫菊酯的CE介导代谢。虽然人类肝脏中可能还有其他水解拟除虫菊酯的酯酶，但本研究结果清楚地表明hCE - 1和hCE - 2是人类水解拟除虫菊酯的CEs。
