鸡蛋中硝基苯检测方法及代谢物在鸡体内动力学研究
摘要
本研究建立了鸡蛋中硝基苯气相色谱的检测方法，并运用该方法对松花江沿岸的主要鸡场和市场的鸡蛋进行了检测。同时，建立了血浆及蛋中硝基苯代谢物HPLC检测方法，并对硝基苯代谢物在蛋鸡血浆中和蛋中的残留消除规律及其对蛋鸡产蛋量的影响进行了研究。
在单次给药试验中，挑选临床检查健康的蛋鸡45只，随机按体重分为15组，每组3只，1组为空白对照组。试验组用胃管经口给予硝基苯50mg／kg·w，于给药前将空白组蛋鸡全部剖杀，并分别于给药后0.25h、0.5h、0.75h、1h、2h、4h、6h、8h、10h、12h、24h、36h、48h、72h剖杀1组，脱颈取血，制备血浆，用于硝基苯及其代谢产物的代谢动力学规律分析。结果表明：蛋鸡内服硝基苯后，氨基酚的血浆药物浓度—时间数据符合一级吸收二室开放式模型，理论方程为C=2.8347e~(-0.0729t)-1.0633e~(-1.6729t)-1.7714e~(-0.194t)，其主要动力学参数为AUC=29.122m／kg．h，C_(max)=1.3015μg／ml，Tp=4.5176h，Tcp=77.469h，Kel=0.3391／h，T_(1／2Ka)=3.5719h，T_(1／2α)=0.4142，T_(1／2β)=9.5068。硝基苯胺的血浆药物浓度—时间数据符合一级吸收一室开放模型，理论方程为C=1122(e~(-0.0706t)-e~(0.9274t))，其主要动力学参数为C_(max)=1.40617μg／ml，Tp=3.2476h，AUC=24.662mg／kg．h，Tcp=73.062h，T_(1／2Ka)=0.74721h，T_(1／2K)=9.81225h。硝基酚的血浆药物浓度—时间数据符合一级吸收二室开放式模型，理论方程为C=3.0071e~(-0.2268t)-0.3732e~(-0.0789t)-2.6339e~(-0.5627t)，其主要动力学参数为AUC=11.977mg／kg．h，C_(max)=1.1844μg／ml，Tp=3.2489h，Tcp=45.87h，Kel=0.1766／h，T_(1／2Ka)=1.2316h，T_(1／2α)=3.0547h，T_(1／2β)=8.7824h。从吸收半衰期与消除半衰期看，三种物质均吸收快，分布消除慢。药动学试验结果表明，硝基苯胺消除最慢，氨基酚其次，硝基酚消除最快。由血药浓度—时间曲线下面积AUC可知，氨基酚和硝基苯胺要比硝基酚在蛋鸡体内分布的快和广。
在多次给药试验中，将120只蛋鸡随机分4组，即3个硝基苯处理组1个对照组，每组30只。3个处理组分别饮水给予硝基苯25mg／L、50mg／L、100mg／L，对照组给予自来水，连续给药10d，之后继续观察10d。结果表明：多次给予硝基苯后，蛋鸡均能正常饮食，蛋重无变化。蛋鸡产蛋量几乎无明显变化。蛋鸡连续口服硝基苯后，血浆中氨基酚、硝基酚代谢消除的快，第4d便检测不到，而硝基苯胺在第7d仍能检测到。各组蛋中硝基苯代谢物TCP(ther)为8.17d～9.30d，通过半衰期计算，停止染毒后蛋中氨基酚、硝基苯胺大约经过8d废弃期才能完全消除。因此建议蛋鸡在饮用受硝基苯污染后的水后应马上更换洁净的饮水，应至少废弃10d的鸡蛋，以确保人们的食用安全。
A gas chromatogram method of detecting nitrobenzene in eggs was established in thisstudy.With this method nitrobenzene was not detected in eggs which were collected in the mainfowl field and market of SongHua river littoral.A high performance liquid chromatography methodof detecting nitrobenzene metabolin was established.The residue and elimination of nitrobenzenemetabolin in eggs-layers' plasma and eggs and the influence on the quantitative of laying eggs werestudied.
In the master single test administration experiment,45 healthy egg-layers were randomly divi-ded to 15 groups with 3 egg-layers in each group.Egg-layers in the treatment groups were orallytaken with nitrobenzene(50mg/kg.bw).3egg-layers in the control group were killed beforeadministration.One group of the treatment groups were killed at 0.25h, 0.5h, 0.75h, 1h, 2h, 4h,6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h.Plasma was prepared to analyze the metabolism kineticsrule of nitrobenzene metabolin.The results showed that the concentration-time course of amino-phenol in plasma could be described by a two-compartment open model with the first orderabsorption after the experimental chickens were orally taken with nitrobenzene, its theoreticalequation was C=2.8347e~(-0.0729t)-1.0633e~(-1.6729t)-1.7714e~~(0.194t),and the main pharmacokineticparameters were as following:AUC=29.122mg/kg.h,C_(max)=1.3015μg/ml,Tp=4.5176h,Tcp=77.469h,Kel=0.3391/h,T_(1/2Ka)=3.5719h, T_(1/2α)=0.4142,T_(1/2β)=9.5068.The concentration-time course ofnitroaniline in plasma could be described by a one-compartment open model with the first orderabsorption, its theoretical equation was- C= 1122 (e~(-0.0706t)-e~(0.9274t)), the main pharmacokineticparameters were as following:C_(max)=1.40617gg/ml,Tp=3.2476h,AUC=24.662mg/kg.h,Tcp=73.062h,T_(1/2Ka)=0.74721 h,T_(1/2K)=9.81225h.The concentration-time course of nitrophenol in plasma could bedescribed by a two-compartment open model with the first order absorption, its theoretical equationwas: C=3.0071e~(0.2268t)-0.3732e~(0.0789t)-2.6339e~(0.5627t), the main pharmacokinetic parameters were asfollowing: AUC=11.977mg/kg.h,C_(max)=1.1844μg/ml, Tp=3.2 489h,Tcp=45.87h,Kel=0.176/h,T_(1/2Ka)=1.2316h,T_(1/2α)=3.0547h,T_(1/2β)=8.7824h.Three metabolites could be seen that they absorpted fast and distributed eliminate slowly.The pharmacokinetic results showed that nitroaniline eliminated themost slowly, aminophenol the next,nitrophenol eliminated the most fast. The results of the AUCvalue showed that aminophenol and nitroaniline distributed faster and wider than the nitrophenol inegg-layers.
In the multiple dosing experiment,120 Roman Brown egg-layers were divided into 3 treatmentgroups and 1 control group randomly with 30 in each group. The Roman Brown egg-layers werefed 25mg/L, 50mg/L, 100mg/L nitrobenzene by drinking water respectively in 3 treatment groupsand those were not fed nitrobenzene in the control group .They were administrated 10 dayssuccessively,and observed 10 days.In the experimental stage,all avian health status,egg layingamout,eating amour and hydroposia arnout were observed.Then the nitrobenzene metabolites in theeggs and plasma were detected by HPLC method.The results indicated that in the multipleadministration experiment,all the fowl could normally diet.The egg weight didn't change.Afterbeing orally administrated nitrobenzene,the egg laying amount was not effected greatly.Aminophenol and nitrophenol eliminated fastly in plasma,they were not detected in the fourthday, but nitroaniline still remained in the seventh day.None of the nitrobenzene metabolites wasdetected in the eggs that were collected at the eighth day after the withdrawal. So, it was suggestedthat egg-layers should be given clean water immediately once they drinked the water containingnitrobenzene and the eggs could be edible after 10 days.
在单次给药试验中，挑选临床检查健康的蛋鸡45只，随机按体重分为15组，每组3只，1组为空白对照组。试验组用胃管经口给予硝基苯50mg／kg·w，于给药前将空白组蛋鸡全部剖杀，并分别于给药后0.25h、0.5h、0.75h、1h、2h、4h、6h、8h、10h、12h、24h、36h、48h、72h剖杀1组，脱颈取血，制备血浆，用于硝基苯及其代谢产物的代谢动力学规律分析。结果表明：蛋鸡内服硝基苯后，氨基酚的血浆药物浓度—时间数据符合一级吸收二室开放式模型，理论方程为C=2.8347e~(-0.0729t)-1.0633e~(-1.6729t)-1.7714e~(-0.194t)，其主要动力学参数为AUC=29.122m／kg．h，C_(max)=1.3015μg／ml，Tp=4.5176h，Tcp=77.469h，Kel=0.3391／h，T_(1／2Ka)=3.5719h，T_(1／2α)=0.4142，T_(1／2β)=9.5068。硝基苯胺的血浆药物浓度—时间数据符合一级吸收一室开放模型，理论方程为C=1122(e~(-0.0706t)-e~(0.9274t))，其主要动力学参数为C_(max)=1.40617μg／ml，Tp=3.2476h，AUC=24.662mg／kg．h，Tcp=73.062h，T_(1／2Ka)=0.74721h，T_(1／2K)=9.81225h。硝基酚的血浆药物浓度—时间数据符合一级吸收二室开放式模型，理论方程为C=3.0071e~(-0.2268t)-0.3732e~(-0.0789t)-2.6339e~(-0.5627t)，其主要动力学参数为AUC=11.977mg／kg．h，C_(max)=1.1844μg／ml，Tp=3.2489h，Tcp=45.87h，Kel=0.1766／h，T_(1／2Ka)=1.2316h，T_(1／2α)=3.0547h，T_(1／2β)=8.7824h。从吸收半衰期与消除半衰期看，三种物质均吸收快，分布消除慢。药动学试验结果表明，硝基苯胺消除最慢，氨基酚其次，硝基酚消除最快。由血药浓度—时间曲线下面积AUC可知，氨基酚和硝基苯胺要比硝基酚在蛋鸡体内分布的快和广。
在多次给药试验中，将120只蛋鸡随机分4组，即3个硝基苯处理组1个对照组，每组30只。3个处理组分别饮水给予硝基苯25mg／L、50mg／L、100mg／L，对照组给予自来水，连续给药10d，之后继续观察10d。结果表明：多次给予硝基苯后，蛋鸡均能正常饮食，蛋重无变化。蛋鸡产蛋量几乎无明显变化。蛋鸡连续口服硝基苯后，血浆中氨基酚、硝基酚代谢消除的快，第4d便检测不到，而硝基苯胺在第7d仍能检测到。各组蛋中硝基苯代谢物TCP(ther)为8.17d～9.30d，通过半衰期计算，停止染毒后蛋中氨基酚、硝基苯胺大约经过8d废弃期才能完全消除。因此建议蛋鸡在饮用受硝基苯污染后的水后应马上更换洁净的饮水，应至少废弃10d的鸡蛋，以确保人们的食用安全。
A gas chromatogram method of detecting nitrobenzene in eggs was established in thisstudy.With this method nitrobenzene was not detected in eggs which were collected in the mainfowl field and market of SongHua river littoral.A high performance liquid chromatography methodof detecting nitrobenzene metabolin was established.The residue and elimination of nitrobenzenemetabolin in eggs-layers' plasma and eggs and the influence on the quantitative of laying eggs werestudied.
In the master single test administration experiment,45 healthy egg-layers were randomly divi-ded to 15 groups with 3 egg-layers in each group.Egg-layers in the treatment groups were orallytaken with nitrobenzene(50mg/kg.bw).3egg-layers in the control group were killed beforeadministration.One group of the treatment groups were killed at 0.25h, 0.5h, 0.75h, 1h, 2h, 4h,6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h.Plasma was prepared to analyze the metabolism kineticsrule of nitrobenzene metabolin.The results showed that the concentration-time course of amino-phenol in plasma could be described by a two-compartment open model with the first orderabsorption after the experimental chickens were orally taken with nitrobenzene, its theoreticalequation was C=2.8347e~(-0.0729t)-1.0633e~(-1.6729t)-1.7714e~~(0.194t),and the main pharmacokineticparameters were as following:AUC=29.122mg/kg.h,C_(max)=1.3015μg/ml,Tp=4.5176h,Tcp=77.469h,Kel=0.3391/h,T_(1/2Ka)=3.5719h, T_(1/2α)=0.4142,T_(1/2β)=9.5068.The concentration-time course ofnitroaniline in plasma could be described by a one-compartment open model with the first orderabsorption, its theoretical equation was- C= 1122 (e~(-0.0706t)-e~(0.9274t)), the main pharmacokineticparameters were as following:C_(max)=1.40617gg/ml,Tp=3.2476h,AUC=24.662mg/kg.h,Tcp=73.062h,T_(1/2Ka)=0.74721 h,T_(1/2K)=9.81225h.The concentration-time course of nitrophenol in plasma could bedescribed by a two-compartment open model with the first order absorption, its theoretical equationwas: C=3.0071e~(0.2268t)-0.3732e~(0.0789t)-2.6339e~(0.5627t), the main pharmacokinetic parameters were asfollowing: AUC=11.977mg/kg.h,C_(max)=1.1844μg/ml, Tp=3.2 489h,Tcp=45.87h,Kel=0.176/h,T_(1/2Ka)=1.2316h,T_(1/2α)=3.0547h,T_(1/2β)=8.7824h.Three metabolites could be seen that they absorpted fast and distributed eliminate slowly.The pharmacokinetic results showed that nitroaniline eliminated themost slowly, aminophenol the next,nitrophenol eliminated the most fast. The results of the AUCvalue showed that aminophenol and nitroaniline distributed faster and wider than the nitrophenol inegg-layers.
In the multiple dosing experiment,120 Roman Brown egg-layers were divided into 3 treatmentgroups and 1 control group randomly with 30 in each group. The Roman Brown egg-layers werefed 25mg/L, 50mg/L, 100mg/L nitrobenzene by drinking water respectively in 3 treatment groupsand those were not fed nitrobenzene in the control group .They were administrated 10 dayssuccessively,and observed 10 days.In the experimental stage,all avian health status,egg layingamout,eating amour and hydroposia arnout were observed.Then the nitrobenzene metabolites in theeggs and plasma were detected by HPLC method.The results indicated that in the multipleadministration experiment,all the fowl could normally diet.The egg weight didn't change.Afterbeing orally administrated nitrobenzene,the egg laying amount was not effected greatly.Aminophenol and nitrophenol eliminated fastly in plasma,they were not detected in the fourthday, but nitroaniline still remained in the seventh day.None of the nitrobenzene metabolites wasdetected in the eggs that were collected at the eighth day after the withdrawal. So, it was suggestedthat egg-layers should be given clean water immediately once they drinked the water containingnitrobenzene and the eggs could be edible after 10 days.
引文
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于桂珍，靳凛，陈辽玲．1998．利用共沸吸附法处理硝基苯废水的研究．辽宁城乡环境科技．18(4)：24-27．
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杨文远，熊楚明．2004．高效液相色谱法对丰产素中硝基酚类和a-萘乙酸的同时测定．农药．4(4)：174-176．
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邹爱东，张群，赵晓春等．2004．HPLC法测定青黛中靛玉红的含量．实用药物与临床．7(3)：13-14．
Albrecht W & Neumann H-G. 1985. Biomonitoring of aniline and nitrobenzene: Hemoglobin-binding in rats and analysis ofadducts. Arch Toxicol. 57: 1-5.
Allenby G, Sharpe RM. 1990. Foster PM. Changes in Sertoli cell function in vitro induced by nitrobenzene. Fundam Appl Toxicol. 14: 364-375.
Altschuh J, Bruggemann R, Santl H. 1999. Henry.s law constants for a diverse set of organic chemicals: Experimental determination and comparison of estimation methods. Chemosphere. 39: 1871-1887.
Albert RE. 1994. Carcinogen risk assessment in the U.S. Environment Protection Agency. CritRev Toxicol. 24:75-85.
Allenby G, Foster PM, & Sharpe RM. 1991. Evaluation of changes in the secretion of immunoactive inhibin by adult rat seminiferous tubules in vitro as an indicator of early toxicant action on spermatogenesis. Fundam Appl Toxicol. 16: 710-724.
Amoore JE&Hautala E. 1983. Odor as an aid to chemical safety:Odor thresholds compared with threshold limit volatilities for 214 industrial chemicals in air and water dilution. Appl Toxicol. 3:272-290.
Amacher DE, Paillet SC, Turner GN. 1980. Point mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells II. Test validation and interpretation. Mutat Res. 72:447-474.
Beagley KW, Black CA, Elson CO. 1991.Strain differences in susceptibility to TNBS-induced colitis. Gastroenterology, 100: A560.
Bond JA, Medinsky MA, Dent JG. 1981. Sex-dependent metabolism and biliary excretion of [2,4-14C] dinitrotoluene in isolated perfused rat livers. Pharmacol Exp Ther. 219(3):598-603.
CossumPA. 1988. Role ofthe red blood cell in drug metabolism. Biopharm Drug Dispos. 9: 321-336.
Derndorf H, Mibohm B. 1999. Modeling of pharmacokinetic / Pharmacodynamic(PK/PD) relationships.Concepts and perspectives. 16:176-185.
Grisham MB, Volkmer C, Tso P, Yamada T.1991. Metabolism of trinitrobenzene sulfonic acid by the rat colon produces reactive oxygen species. Gastroenterology. 101: 540 - 7.
Haigler B E.Spain J C. 1991.Biotransmation of nitrobenzene by bacteria containing toluene degradation pathways. Appl.Environ.Microbiol. 57(11: 3156-3161.
Hinhman C A, Matsumoto H, Simmons T W, et al. 1991.Intrahepatic conversion of glutathione conjugate to its mercapturic acid. Biol Chem. 266: 22179-22185.
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