Metabolism of deltamethrin and cis- and trans-permethrin by human expressed cytochrome P450 and carboxylesterase enzymes

1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes.

2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CL_int) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5. None of the pyrethroids were metabolised by CYP2A6, CYP2E1, CYP3A7 or CYP4A11.

3. DLM, CPM and TPM were metabolised by both human CES1 and CES2 enzymes.

4. Apparent CL_int values for pyrethroid metabolism by CYP and CES enzymes were scaled to per gram of adult human liver using abundance values for microsomal CYP enzymes and for CES enzymes in liver microsomes and cytosol. TPM had the highest and CPM the lowest apparent CL_int values for total metabolism (CYP and CES enzymes) per gram of adult human liver.

5. Due to their higher abundance, all three pyrethroids were extensively metabolised by CES enzymes in adult human liver, with CYP enzymes only accounting for 2%, 10% and 1% of total metabolism for DLM, CPM and TPM, respectively.

     

溴氰菊酯对PC12细胞Fas、FasL、TNFR1蛋白及凋亡的影响

背景与目的 :探讨溴氰菊酯诱导神经细胞凋亡及其神经毒作用机制。 材料与方法 :用免疫细胞化学法定性检测给予不同剂量水平(10 -4mol/L ,10 -5mol/L ,10 -6mol/L)的溴氰菊酯24h后 ,Fas、FasL、TNFR1蛋白在PC12细胞中的表达 ;流式细胞仪定量检测给予溴氰菊酯24h和48h后 ,Fas、FasL、TNFR1蛋白在PC12细胞中的相对表达量阳性细胞率(rateofpositivecells ,RPC)和平均荧光强度(meanfluorescenceintensity,MFI)及PC12细胞的凋亡率。 结果 :①Fas、FasL、TNFR1蛋白在对照组和各剂量组均为阳性表达 ,但镜下未见各蛋白在各组之间的差异表达。流式细胞仪检测发现 :染毒24h后 ,Fas、FasL蛋白在各组的表达没有差异 ,而TNFR1蛋白在中剂量和高剂量组的表达与对照组比较有升高 ;染毒48h后 ,Fas、FasL、TNFR1蛋白在高剂量组表达(MFI分别为42.85±8.4、37.91±1.65、8.09±1.83)与各自对照组比较均有升高。②染毒24h后 ,各剂量组凋亡率没有升高 ;染毒48h后 ,高剂量组凋亡率与对照组凋亡率比较有升高。③染毒48h组细胞凋亡率与溴氰菊酯浓度、Fas、Fasl蛋白含量有直线相关关系。 结论 :溴氰菊酯可能通过死亡受体Fas诱导PC12细胞凋亡。     

Metabolism of deltamethrin and cis- and trans-permethrin by rat and human liver microsomes,liver cytosol and plasma preparations

1. The metabolism of deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in liver microsomes, liver cytosol and plasma from male Sprague–Dawley rats aged 15, 21 and 90 days and from adult humans.

2. DLM and CPM were metabolised by rat hepatic microsomal cytochrome P450 (CYP) enzymes and to a lesser extent by microsomal and cytosolic carboxylesterase (CES) enzymes, whereas TPM was metabolised to a greater extent by CES enzymes.

3. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes.

4. The metabolism of pyrethroids by cytosolic CES enzymes contributes to the overall hepatic clearance of these compounds.

5. DLM, CPM and TPM were metabolised by rat, but not human, plasma CES enzymes.

6. This study demonstrates that the ability of male rats to metabolise DLM, CPM and TPM by hepatic CYP and CES enzymes and plasma CES enzymes increases with age. In all instances, apparent intrinsic clearance values were lower in 15 than in 90?day old rats. As pyrethroid-induced neurotoxicity is due to the parent compound, these results suggest that DLM, CPM and TPM may be more neurotoxic to juvenile than to adult rats.

     

Comparison of deltamethrin tablet formulation with liquid deltamethrin and permethrin for bednet treatment in The Gambia

The study aim was to compare three formulations, tablet deltamethrin, liquid deltamethrin and liquid permethrin, for their impact on vector behaviour and persistence. Product acceptance, perceived side-effects and user's perceptions of effectiveness were also investigated. At the beginning of the 1998 rainy season, 255 nets in a Gambian village were dipped in one of the three insecticides. Chemical residue analysis immediately after dipping showed that the target doses were reached for the liquid insecticides, but tablet deltamethrin deposited significantly less. Insecticide persistence at 5 months, however, was highest for the tablet formulation. Susceptibility tests established that Anophelines in this area were sensitive to both insecticides. All three formulations appeared effective as very few live Anophelines, or other mosquitoes, were caught under the treated nets. This conclusion was supported by the bioassay data with both deltamethrin formulations giving over 90% mortality soon after dipping and at 3 months, and at 5 months 70.8 and 79.6% were obtained for deltametrin liquid and tablet, respectively. Permethrin appeared less effective at all times (72.4, 86.8, 59.0%). There were no serious side-effects reported by the villagers following dipping. All three treatments were perceived as effective by the majority (92%) of users and most (93%) wanted to use the insecticide again. Deltamethrin tablets thus appear as good as permethrin for treating bednets in The Gambia. In addition, a tablet formulation is considerable easier to pack and distribute.     

Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat.

Deltamethrin (DLT) is a type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based pharmacokinetic (PBPK) model for DLT was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (brain, gastrointestinal [GI] tract, liver, and rapidly perfused tissues) and diffusion-limited (fat, blood/plasma, and slowly perfused tissues) rate equations. The blood was divided into plasma and erythrocytes. Cytochrome P450-mediated metabolism was accounted for in the liver and carboxylesterase (CaE)-mediated metabolism in plasma and liver. Serial blood, brain, and fat samples were taken for DLT analysis for up to 48 h after adult rats received 2 or 10 mg DLT/kg po. Hepatic biotransformation accounted for approximately 78% of these administered doses. Plasma CaEs accounted for biotransformation of approximately 8% of each dosage. Refined PBPK model forecasts compared favorably to the 2- and 10-mg/kg po blood, plasma, brain, and fat DLT profiles, as well as profiles subsequently obtained from adult rats given 1 mg/kg iv. DLT kinetic profiles extracted from published reports of oral and iv experiments were also used for verification of the model's simulations. There was generally good agreement in most instances between predicted and the limited amount of empirical data. It became clear from our modeling efforts that there is considerably more to be learned about processes that govern GI absorption and exsorption, transport, binding, brain uptake and egress, fat deposition, and systemic elimination of DLT and other pyrethroids. The current model can serve as a foundation for construction of models for other pyrethroids and can be improved as more definitive information on DLT kinetic processes becomes available.     

混合喷洒拟菊酯与有机磷杀虫剂对施药员健康影响的研究

为探讨混合喷洒拟菊酯与有机磷对施药员健康的影响,作者等在河北产棉区进行了流行病学调查和生物监测研究。混合喷洒拟菊酯与有机磷和单纯喷洒拟菊酯两组人群在不良反应率和中毒率上未见明显差别。混喷组施药员全血胆碱酯酶活性也未见明显变化。混喷组施药员尿中拟菊酯原型的排泄有高于单纯喷洒组的趋势,尿中代谢物Br_2A未见增加。结果表明,在本文观察的接触水平下,混合喷洒拟菊酯与有机磷杀虫剂对施药员健康的影响未超过单纯喷洒拟菊酯者。     

拟除虫菊酯对中华按蚊繁殖率和生存力影响的观察报告

用拟除虫菊酯亚致死剂量处理中华按蚊,显示该蚊的生存力和繁殖率降低。以胺菊酯或溴氰菊酯处理中华按蚊,产卵的胚胎发育减慢。溴氰菊酯致死的部分中华按蚊幼虫体长缩短。     

急性拟除虫菊酯中毒的临床表现及诊断

国外迄今尚未见有急性拟除虫菊酯中毒的临床报告。国内医学文献自1982年至1988年则已报道急性拟除虫菊酯中毒共573例,其中生产性中毒229例,意外性中毒344例。以急性溴氰菊酯中毒最为多见(325例),其次为戊氰菊酯(196例)及氯氰菊酯(45例)等急性中毒。本文对573例急性拟除虫菊酯中毒的临床表现进行综述与分析,并探讨其诊断分级与鉴别诊断,为制定职业性急性拟除虫菊酯中毒诊断标准提供参考。     

溴氰菊酯致大鼠慢性中毒的肝组织形态学观察

目的探讨溴氰菊酯对大鼠肝组织结构的慢性损伤作用。方法选取大鼠32只,随机分为空白对照组(Ⅰ组)、橄榄油对照组(Ⅱ组)、溴氰菊酯1.56 mg/kg组(Ⅲ组)、溴氰菊酯6.25 mg/kg组(Ⅳ组),每组8只。Ⅲ、Ⅳ组连续6个月经口灌胃染毒,Ⅱ组只给予相当剂量的橄榄油,观察大鼠染毒期间行为学变化,测定肝脏器系数,肝组织切片经苏木精-伊红染色和PAS染色,观察肝细胞形态学变化和肝细胞糖原含量的变化。结果染毒组大鼠出现流涎、大汗、立毛等中毒症状。苏木精-伊红染色显示Ⅲ、Ⅳ组肝细胞胞浆疏松,内可见脂滴,肝血窦淤血。染毒组大鼠肝细胞的糖原含量有不同程度降低,Ⅳ组与Ⅰ、Ⅱ、Ⅲ组相比,Ⅲ组和Ⅰ组相比差异有统计学意义(F=9.015,q=3.675~10.058,P<0.05);但Ⅲ组与Ⅱ组比较,差异无统计学意义(q=0.672,P>0.05)。Ⅲ、Ⅳ组肝脏器系数与其他各组比较,差异均有统计学意义(F=10.737,q=3.945~9.968,P<0.05)。结论长期低剂量摄入溴氰菊酯可造成大鼠肝组织的慢性损伤,并具有剂量-效应关系。     

Synergist efficacy of piperonyl butoxide with deltamethrin as pyrethroid insecticide on Culex tritaeniorhynchus (Diptera: Culicidae) and other mosquitoe species

Continuous and indiscriminate use of pesticides, especially in tropical countries for public health or agriculture purpose, has led many vector populations to become resistant to organochlorides, organophosphates, and even to carbamates and pyrethroids. Development of resistance by a vector population has been one of the reasons for the failure of the control measures in many countries. This investigation demonstrates the efficacy of piperonyl-butoxide (PBO) with deltamethrin, as pyrethroid insecticide, against the field-collected mosquitoe larvae of five species, Aedes aegypti, Anopheles culicifacies, An. stephensi, An. vagus, and Culex quinqufasciatus, and two morphological variants of Cx. tritaeniorhynchus (type A from grand pools of Mysore city and type B from rice fields of Mandya district). For testing the synergistic effect of PBO, stock solutions of deltamethrin and PBO were mixed in 1:6 ratio. The synergistic ratio and the percent suppression in deltamethrin tolerance were calculated by using LC(50) values. From the results, it is clear that, PBO is an effective synergist with deltamethrin against all of species undertaken in this investigation. So, it is suggested that PBO is a good synergist in this area for decreasing the use of pesticides in environment in vector control.