Nallani Gopinath C, Chandrasekaran Appavu, Kassahun Kelem, Shen Li, ElNaggar Shaaban F, Liu Zhiwei
Global Regulatory Sciences, FMC Agricultural Solutions, 701 Princeton South Corporate Center, Ewing, NJ 08628, USA.
Global Regulatory Sciences, FMC Agricultural Solutions, 701 Princeton South Corporate Center, Ewing, NJ 08628, USA.
Toxicol Appl Pharmacol. 2018 Jan 1;338:65-72. doi: 10.1016/j.taap.2017.11.010. Epub 2017 Nov 13.
Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (<5years and >18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CL) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean V(±SD) for the formation of 4'-OH-BIF in juvenile rat hepatic microsomes was 25.0±1.5pmol/min/mg which was significantly lower (p<0.01) compared to that of adult rats (86.0±17.7pmol/min/mg). However, the mean K values for juvenile (19.9±6.6μM) and adult (23.9±0.4μM) rat liver microsomes were similar. On the other hand, in juvenile human hepatic microsomes, V for the formation of 4'-OH-BIF (73.9±7.5pmol/min/mg) was significantly higher (p<0.05) than that of adults (21.6±0.6pmol/min/mg) albeit similar K values (10.5±2.8μM and 8.9±0.6μM) between the two age groups. The trends in the formation kinetics of TFP acid were similar to those of 4'-OH-BIF between the species and age groups, although the differences between juveniles and adults were less pronounced. The data also show that metabolism of bifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CL values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0±7.2 and 166.7±20.5μl/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0±4.0 and 21.3±1.2μl/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes.
联苯菊酯是一种拟除虫菊酯类杀虫剂，在大鼠和人类肝脏微粒体中会发生氧化代谢生成4'-羟基联苯菊酯（4'-OH-BIF），并发生水解生成TFP酸。在本研究中，通过将联苯菊酯分别与幼年和成年大鼠（出生后第15天和第90天）以及人类（<5岁和>18岁）肝脏微粒体孵育后，测定4'-OH-BIF和TFP酸的生成速率，来确定大鼠和人类中联苯菊酯的年龄依赖性代谢。此外，在另一个实验中通过底物消耗法测定了联苯菊酯的体外肝脏内在清除率（CL）。幼年大鼠肝脏微粒体中4'-OH-BIF生成的平均V（±标准差）为25.0±1.5pmol/分钟/毫克，与成年大鼠（86.0±17.7pmol/分钟/毫克）相比显著更低（p<0.01）。然而，幼年（19.9±6.6μM）和成年（23.9±0.4μM）大鼠肝脏微粒体的平均K值相似。另一方面，在幼年人类肝脏微粒体中，4'-OH-BIF生成的V（73.9±7.5pmol/分钟/毫克）显著高于成年人（21.6±0.6pmol/分钟/毫克）（p<0.05），尽管两个年龄组之间的K值相似（10.5±2.8μM和8.9±0.6μM）。在不同物种和年龄组之间，TFP酸生成动力学的趋势与4'-OH-BIF相似，尽管幼年和成年之间的差异不太明显。数据还表明，在大鼠和人类肝脏微粒体中，联苯菊酯的代谢主要通过氧化途径进行，水解途径的贡献相对较小（约30%）。通过监测底物消耗测定的，用NADPH强化的幼年和成年大鼠肝脏微粒体中联苯菊酯的CL值分别为42.0±7.2和166.7±20.5μl/分钟/毫克，人类肝脏微粒体的相应值分别为76.0±4.0和21.3±1.2μl/分钟/毫克。数据表明在联苯菊酯的年龄依赖性代谢方面存在主要的物种差异。在人类肝脏微粒体中，联苯菊酯在幼年中的代谢速率比成年人高得多，而在大鼠肝脏微粒体中情况似乎相反。
