对氧磷酶1对敌敌畏毒代动力学的影响

摘要

目的 通过研究对氧磷酶1 (PON1)对有机磷药物代谢动力学影响,证明PON1是有前景的有机磷催化清除剂.方法 将Wistar大鼠随机分成:染毒组(A组):腹腔注射敌敌畏(DDVP) 10 mg/kg; PON1预处理组(B组):尾静脉注射纯化兔血清PON1 9 600 U/kg,30 min后腹腔注射DDVP 10 mg/kg;治疗组(C组):DDVP 10 mg/kg腹腔注射后,立即(＜2 min)尾静脉注射阿托品0.05 mg/kg+解磷定120 mg/kg;联合治疗组(D组):尾静脉注射PON1 9 600 U/kg,30 min后腹腔注射DDVP 10 mg/kg,立即尾静脉注射阿托品0.05 mg/kg+解磷定120 mg/kg.于各时间点采血,液-质联用法测定血中敌敌畏含量.比较同一时间点敌敌畏浓度及各组的毒代动力学参数.结果 对相同时间点DDVP浓度进行单因素方差分析,A组与C组间及B组与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(P＜0.05).对4组的毒代动力学参数进行一元方差分析,曲线下面积数比较A组与C组间及B组与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.平均保留时间数据4组间差异无统计学意义.峰浓度值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(P＜0.05).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的曲线下面积(0→∞)及峰浓度值降低,但对平均保留时间影响不大,所以PON1可以明显降低敌敌畏入血量,降低峰浓度.%Objective To investigate the effect of paraoxonase-1 (PON1) on dichlorvos toxicokinetics, to prove that it is a promising scavenger on organophosphates intoxication. Methods Wistar rats were randomly divided to 4 groups:dichlorvos administration group (A group):dichlorvos dissolved in com oil was injected by intraperitoneal in a dose of 10 mg/kg. Paraoxonase-1 (PON1 ) pretreatment group (B group): PON1 was injected in the tail vein in a dose of 9 600 U/kg before 30 min of dichlorvos administration. Treatment group (C group ): atropine 0.05 mg/kg and pyraloxime chloride (PAM-CI) 120 mg/kg were injected via tail vein within 2 min after dichlorvos administration. Co-treatment group (D group): PON1 was injected in the tail vein in a dose of 9 600 U/kg before 30 min of 10 mg/kg dichlorvos administration by intraperitoneal,atropine 0.05 mg/kg and pyraloxime chloride (PAM-CI) 120 mg/kg were injected via tail vein in 2 min after dichlorvos administration. Blood was collected, plasma dichlorvos concentration was detected by liquid chromatography-mass spectra (LC-MS) method. Dichlorvos concentration was detected, toxicokinetics parameters were calculated in a statistical moment model. Results AUC (0-? ∞) in group B was statistically different from that of group A and C (P < 0.05), while it was not different from group D (P > 0.05); there was no statistical difference between group A and group C (P > 0.05). The statistical results of Cmax were the same as AUC (0-?∞) (P > 0.05). There were no difference of MRT among four groups (P > 0.05). Conclusion PON1 could decrease the amount of dichlorvos that entered blood, lowed down the peak concentration,while atropine + PAM-CI did not affect metabolism of dichlorvos.