Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: Differential oxidative and hydrolytic metabolism by humans and rats
Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: Differential oxidative and hydrolytic metabolism by humans and rats
复制标题
DOI：
10.1124/dmd.106.010058
复制
发表时间：
2006-10-01
影响因子：
3.9
通讯作者：
Ross, Matthew K.
中科院分区：
文献类型：
--
作者：
Godin, Stephen J.;Scollon, Edward J.;Ross, Matthew K.
拟除虫菊酯是一种神经毒性农药，其药代动力学行为对其效力起着重要作用。这项研究考察了氰戊菊酯和溴氰菊酯从大鼠和人肝微粒体中的消除情况。在NADPH存在和不存在的情况下，采用亲本耗竭方法来评估生物转化途径、清除率和内在肝脏清除率的物种差异。氰戊菊酯主要通过NADPH依赖的氧化代谢在大鼠和人肝微粒体中被消除。按每公斤体重计算，啮齿类动物体内氰戊菊酯的固有肝清除量(CLINT)估计是人类的3倍。在大鼠肝微粒体中，溴氰菊酯也主要通过NADPH依赖的氧化代谢来消除；而在人肝微粒体中，溴氰菊酯几乎完全通过NADPH非依赖的水解代谢来消除。据估计，按每公斤体重计算，人体对溴氰菊酯的反应速度比大鼠快2倍。用纯化的大鼠和人的羧酸酯酶(CES)进行代谢，进一步考察了溴氰菊酯和氰戊菊酯在降解过程中的物种差异。CE代谢结果表明，人羧酸酯酶1(HCE-1)对溴氰菊酯的代谢活性明显高于1类大鼠CES A、B和2类人CE(HCE-2)，但水解酶A对氰戊菊酯的代谢速度是HCE-1的2倍，而水解酶B和HCE-1对氰戊菊酯的代谢速度相同。这些研究表明，溴氰菊酯在大鼠和人肝微粒体中的体外生物转化途径存在显著的物种差异，部分原因是大鼠和人的羧酸酯酶的内在活性不同。
Pyrethroids are neurotoxic pesticides whose pharmacokinetic behavior plays a role in their potency. This study examined the elimination of esfenvalerate and deltamethrin from rat and human liver microsomes. A parent depletion approach in the presence and absence of NADPH was used to assess species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The intrinsic hepatic clearance ( CLINT) of esfenvalerate was estimated to be 3-fold greater in rodents than in humans on a per kilogram body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes; however, in human liver microsomes, deltamethrin was eliminated almost entirely via NADPH-independent hydrolytic metabolism. The CLINT for deltamethrin was estimated to be 2-fold more rapid in humans than in rats on a per kilogram body weight basis. Metabolism by purified rat and human carboxylesterases ( CEs) were used to further examine the species differences in hydrolysis of deltamethrin and esfenvalerate. Results of CE metabolism revealed that human carboxylesterase 1 ( hCE-1) was markedly more active toward deltamethrin than the class 1 rat CEs hydrolase A and B and the class 2 human CE ( hCE-2); however, hydrolase A metabolized esfenvalerate 2-fold faster than hCE-1, whereas hydrolase B and hCE-1 hydrolyzed esfenvalerate at equal rates. These studies demonstrate a significant species difference in the in vitro pathways of biotransformation of deltamethrin in rat and human liver microsomes, which is due in part to differences in the intrinsic activities of rat and human carboxylestersases.