【作者】 王娜娜；

【导师】 赵敏；

【作者基本信息】 中国医科大学 ， 急诊医学， 2010， 硕士

【摘要】 目的通过研究对氧磷酶-1对有机磷药物代谢动力学影响,证明对氧磷酶-1是有前景的有机磷催化清除剂。方法Wistar大鼠,40只,雌雄各半,随机分成4组：染毒组：腹腔注射DDVP10mg/kg。PON1预处理组：大鼠尾静脉注射PON1 9600U/kg,30min后腹腔注射DDVP10mg/kg;治疗组：DDVP10mg/kg腹腔注射后,立即(<2min)尾静脉注射阿托品0.05mg/kg+解磷定120mg/kg。联合治疗组：大鼠尾静脉注射PON1 9600U/kg,30min后腹腔注射DDVP10mg/kg,立即尾静脉注射阿托品0.05mg/kg+解磷定120mg/kg。分别于染毒前、染毒后3min、5min、10min、20min、30min、1h、2h、4h、6h分别经眶后静脉采血0.2ml。测定全血胆碱酯酶活性和液-质联用法测定血中敌敌畏含量。同一时间点胆碱酯酶活性值采用一元方差分析,毒代学参数采用3p97软件合成。结果1.胆碱酯酶活性：对4组相同时间点上数据进行双因素方差分析。因素“PON1”,p<0.05,可以认为PON1效应差异显著,PON1可明显改善胆碱酯酶抑制水平；因素"atropine+PAM"p<0.05,可以认为"atropine+PAM"效应差异显著,明显改善胆碱酯酶抑制水平；因素“PON1”和"atropine+PAM"在所有时间点上p<0.05,所以两个因素交互作用显著。2.敌敌畏液质连用检测方法学：本实验条件下,约在4.1min处检测到敌敌畏的特征峰,约在4.9min处检测到内标吲哚美辛的特征峰。经线性回归分析,得敌敌畏浓度与峰面积的回归方程为：Y=-0.0404282+0.16048*X,R2=0.9945,线性范围为0.1μg/ml—6μg/ml。3.大鼠体内敌敌畏浓度：将同一时间点数值与A组数值进行独立样本t-检验。B组、C组与A组有显著差异。对相同时间点上4组的数据进行单因素方差分析,A组与C组无显著性差异,B组与D组无显著性差异,A组、C组与B组、D组间有显著性差异。4.敌敌畏毒物代谢动力学参数：毒代动力学分析采用统计矩模型。对4组的毒代动力学参数进行一元方差分析,曲线下面积数据A组与C组间无显著性差异,B组与D组间无显著性差异。A组、C组与B组、D组有显著性差异。平均保留时间数据4组间无显著性差异。峰浓度值经一元方差分析,A组和C组间差异无统计学意义,B组和D组间差异无统计学意义。A组、C组与B组、D组间差异有统计学意义。结论纯化兔血清PON1可以明显改善大鼠体内胆碱酯酶抑制水平。对敌敌畏毒物代谢动力学参数影响表现为较小AUC(0→∞)、降低Cmax值,但对MRT影响不大,所以纯化兔血清PON1可以明显降低敌敌畏入血量,降低峰浓度。更多还原

【Abstract】 ObjectiveIn the experiment, we studied the paraoxonase-1(PON1) effect on dichlorvos toxicokinetics to prove that it is a promising scavenger of organophosphates.Materials and Methods40 clean grade male Wistar rats were assigned to 4 groups:dichlorvos administration group (A group):dichlorvos dissolved in corn oil was injected by intraperitoneal in a dose of 10mg/kg. Paraoxonase-1 (PON1) pretreatment group (B group):PON1 was injected in the tail vein in a dose of 9600U/kg before 30min of dichlorvos administration. Treatment group(C group):atropine 0.05mg/kg and pyraloxime chloride (PAM-CI) 120mg/kg were injected via tail vein within 2min after dichlorvos administration. Co-treatment group (D group):PON1 was injected in the tail vein in a dose of 9000U/kg before 30min of 10mg/kg dichlorvos administration by intraperitoneal, atropine 0.05mg/kg and pyraloxime chloride (PAM-CI) 120mg/kg were injected via tail vein in 2 min after dichlorvos administration. Blood was collected at 3min,5min, 10min,20min,30min, 1h,2h,4h and 6h after administration from the eye veins. Plasma dichlorvos concentration was detected by liquid chromatography-mass spectra (LC-MS) method. Toxicokinetics parameters were calculated in a statistical moment model.ResultsAUC (0→∞) in group B was statistically different from that in group A and C, while it was not different from group D; there was no statistical difference between group A and group C. The statistical results of Cmax were the same as AUC (0→∞). There were no differences of MRT between four groups.ConclusionsPON1 can decrease the amount of dichlorvos that entered blood, lowed down the peak concentration, while atropine+PAM-CI does not affect metabolism of dichlorvos.更多还原