有机磷农药中毒后全血、红细胞乙酰胆碱酯酶和血清丁酰胆碱酯酶活性变化关系分析
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摘要
急性有机磷农药中毒(AOPP)是一个威胁人类健康的全球性问题。不同国家和地区报道的AOPP死亡率从4-30％不等，我国的救治死亡率平均为10％，远远高于国外。
目前，临床上对AOPP患者大多观测其血清丁酰胆碱酯酶(BuChE)的活性变化情况，且诊断中毒程度分级标准采用的是乙酰胆碱酯酶(AChE)的中毒程度分级诊断标准，一直以来国家没有建立统一的BuChE对OP中毒程度的诊断标准。那么，临床上采用AChE中毒程度的分级诊断标准作为BuChE检测诊断中毒程度的分级诊断标准是否正确?这两种酶的关系如何?是否可以建立能以BuChE诊断中毒程度的分级诊断标准?为达研究目的，采用对体外健康人血及动物进行一系列的有机磷农药染毒实验，观测血中AChE和BuChE的活性变化情况并分析二者活性变化的相关性，为临床诊断、治疗提供实验依据。
实验结果：
1、体外健康人血DDVP染毒实验：随着浓度降低，DDVP对全血、红细胞AChE和血清BuChE活性抑制作用均相应出现减弱，BuChE活性较AChE活性低，两种酶的活性变化趋势基本是平行的，呈直线回归关系，两者差异是显著的(P＜0.05)。采用t检验分析，人全血和红细胞加入不同浓度DDVP后AchE活性变化无显著性差异(p＞0.05)。
2、动物染毒实验：大鼠DDVP染毒实验，分不给予阿托品的轻度(DDVP2mg／kg)、中度(DDVP5mg／kg)、重度(DDVP7mg／kg)染毒组及给予阿托品的重度染毒组；大耳白兔DDVP(6mg／kg)染毒实验；大鼠乐果(4mg／kg)染毒实验。实验结果显示：全血、红细胞AChE和血清BuChE活性均出现降低，两种酶的活性变化趋势基本是平行的，降低程度与染毒剂量的大小基本呈线性关系。BuChE活性下降更明显(P＜0.05)，在不同染毒剂量下各时间点的全血和红细胞中AchE活性变化无显著性差异(p＞0.05)。
实验结果说明，OP中毒后，AChE和BuChE的活性变化趋势是平行的，但是，OP对BuChE的抑制程度更明显，血清BuChE活性变化不能反映OP中毒程度，如以血清BuChE活性作为临床诊断指标，需要加上一个修正系数。
Acute organophosphorus pesticide poisoning (OP) is a serious global threat to the human health nowadays, it's reported that the OP mortality rate ranges from 4% to 30% among different countries and regions, and the mortality rate of China is around 10%, much higher than that reported abroad.
At present, the AChE government diagnostic classification standard of China is clinically employed to diagnose OP patients, most of whose butyryl cholinesterase (BuChE) activity changes in serum are simultaneously observed, but there hasn't be a universal government diagnostic classification standard made according to the BuChE activity changes in China. Then, is it right to employ the AChE poisoning diagnostic classification standard as the examination standard of the BuChE poisoning diagnostic classification? How is the relationship between AChE and BuChE? Whether BuChE activity changes could be employed as the poisoning diagnostic classification standard? In order to solve all the problems above, a series of experiments of healthy human blood and animals of organophosphorus pesticide intoxication in vitro are made to observe the activity changes of AChE and BuChE and to analyze the correlation of their activity changes, providing experimental evidence for the clinical diagnosis and treatment.
Experimental results:
1 Healthy human blood DDVP intoxication experiment in vitro: As the DDVP density decreased, both of its activity inhibitions against AChE in whole blood and red cells and BuChE in serum correspondingly weakened. BuChE possessed a lower activity than AChE, and they shared the approximately paralleled activity change tendency, displaying their linear regression relation (p <0.05). AChE activity, analyzed by t test, had no significant variance in whole blood and red cells with different densities of DDVP (p>0.05).
2 Animal intoxication experiment: There were three animal intoxication experiments: the big rats DDVP intoxication experiment with four intoxication groups, the light group with no Atropine (DDVP 2mg/kg), the moderate group with no Atropine (DDVP 5mg/kg), the severe group with no Atropine (DDVP 7mg/kg) and the Atropine group; the big-ear albino rabbits intoxication experiment(DDVP 6mg/kg) and the big rats Rogor intoxication experiment (Rogor 4mg/kg). According to the experiment results, both of the activity inhibitions of AChE in whole blood and red cells and BuChE in serum decreased, and the decreasing level shared a linear relationship with the intoxication dosage on the whole, the BuChE activity possessed a more dominant decrease (p <0.05 ) , and AChE and BuChE showed the approximately paralleled activity change tendency. AChE activity had no significant variance in whole blood and red cells at different times in all the experiments (p>0.05).
The experimental results suggest that AChE and BuChE share the paralleled activity change tendency after OP. The BuChE activity change couldnot reflect the OP level, but the inhibition of OP against BuChE is more dominant, if the BuChE activity in serum was employed as the clinical diagnostic criteria, one more adjusting coefficient should be added.
目前，临床上对AOPP患者大多观测其血清丁酰胆碱酯酶(BuChE)的活性变化情况，且诊断中毒程度分级标准采用的是乙酰胆碱酯酶(AChE)的中毒程度分级诊断标准，一直以来国家没有建立统一的BuChE对OP中毒程度的诊断标准。那么，临床上采用AChE中毒程度的分级诊断标准作为BuChE检测诊断中毒程度的分级诊断标准是否正确?这两种酶的关系如何?是否可以建立能以BuChE诊断中毒程度的分级诊断标准?为达研究目的，采用对体外健康人血及动物进行一系列的有机磷农药染毒实验，观测血中AChE和BuChE的活性变化情况并分析二者活性变化的相关性，为临床诊断、治疗提供实验依据。
实验结果：
1、体外健康人血DDVP染毒实验：随着浓度降低，DDVP对全血、红细胞AChE和血清BuChE活性抑制作用均相应出现减弱，BuChE活性较AChE活性低，两种酶的活性变化趋势基本是平行的，呈直线回归关系，两者差异是显著的(P＜0.05)。采用t检验分析，人全血和红细胞加入不同浓度DDVP后AchE活性变化无显著性差异(p＞0.05)。
2、动物染毒实验：大鼠DDVP染毒实验，分不给予阿托品的轻度(DDVP2mg／kg)、中度(DDVP5mg／kg)、重度(DDVP7mg／kg)染毒组及给予阿托品的重度染毒组；大耳白兔DDVP(6mg／kg)染毒实验；大鼠乐果(4mg／kg)染毒实验。实验结果显示：全血、红细胞AChE和血清BuChE活性均出现降低，两种酶的活性变化趋势基本是平行的，降低程度与染毒剂量的大小基本呈线性关系。BuChE活性下降更明显(P＜0.05)，在不同染毒剂量下各时间点的全血和红细胞中AchE活性变化无显著性差异(p＞0.05)。
实验结果说明，OP中毒后，AChE和BuChE的活性变化趋势是平行的，但是，OP对BuChE的抑制程度更明显，血清BuChE活性变化不能反映OP中毒程度，如以血清BuChE活性作为临床诊断指标，需要加上一个修正系数。
Acute organophosphorus pesticide poisoning (OP) is a serious global threat to the human health nowadays, it's reported that the OP mortality rate ranges from 4% to 30% among different countries and regions, and the mortality rate of China is around 10%, much higher than that reported abroad.
At present, the AChE government diagnostic classification standard of China is clinically employed to diagnose OP patients, most of whose butyryl cholinesterase (BuChE) activity changes in serum are simultaneously observed, but there hasn't be a universal government diagnostic classification standard made according to the BuChE activity changes in China. Then, is it right to employ the AChE poisoning diagnostic classification standard as the examination standard of the BuChE poisoning diagnostic classification? How is the relationship between AChE and BuChE? Whether BuChE activity changes could be employed as the poisoning diagnostic classification standard? In order to solve all the problems above, a series of experiments of healthy human blood and animals of organophosphorus pesticide intoxication in vitro are made to observe the activity changes of AChE and BuChE and to analyze the correlation of their activity changes, providing experimental evidence for the clinical diagnosis and treatment.
Experimental results:
1 Healthy human blood DDVP intoxication experiment in vitro: As the DDVP density decreased, both of its activity inhibitions against AChE in whole blood and red cells and BuChE in serum correspondingly weakened. BuChE possessed a lower activity than AChE, and they shared the approximately paralleled activity change tendency, displaying their linear regression relation (p <0.05). AChE activity, analyzed by t test, had no significant variance in whole blood and red cells with different densities of DDVP (p>0.05).
2 Animal intoxication experiment: There were three animal intoxication experiments: the big rats DDVP intoxication experiment with four intoxication groups, the light group with no Atropine (DDVP 2mg/kg), the moderate group with no Atropine (DDVP 5mg/kg), the severe group with no Atropine (DDVP 7mg/kg) and the Atropine group; the big-ear albino rabbits intoxication experiment(DDVP 6mg/kg) and the big rats Rogor intoxication experiment (Rogor 4mg/kg). According to the experiment results, both of the activity inhibitions of AChE in whole blood and red cells and BuChE in serum decreased, and the decreasing level shared a linear relationship with the intoxication dosage on the whole, the BuChE activity possessed a more dominant decrease (p <0.05 ) , and AChE and BuChE showed the approximately paralleled activity change tendency. AChE activity had no significant variance in whole blood and red cells at different times in all the experiments (p>0.05).
The experimental results suggest that AChE and BuChE share the paralleled activity change tendency after OP. The BuChE activity change couldnot reflect the OP level, but the inhibition of OP against BuChE is more dominant, if the BuChE activity in serum was employed as the clinical diagnostic criteria, one more adjusting coefficient should be added.
引文
1 R. I. Krieger, Handbook of Pesticide Toxicology, Academic Press, San Diego, 2001.
2 T. C. Kwong, Organophosphate pesticides: biochemistry and clinical toxicology, Ther. Drug Monit. 2002; 24: 144-149.
3 M. Lotti, Clinical toxicology of anticholinesterase agents in humans. In: R. I. Krieger, Editor, Handbook of Pesticide Toxicology, Academic Press, San Diego 2001, 1043-1085.
4 D. Gunnell and M. Eddleston, Suicide by intentional ingestion of pesticides: a continuing tragedy in developing countries, Int. J. Epidemiol. 2003; 32: 902-909.
5 J. Cocker, H. J. Mason, S. J. Garfitt and K. Jones, Biological monitoring of exposure to organophosphate pesticides, Toxicol. Lett. 2002; 134: 97-103.
6 M. Eddleston, L. Karalliedde, N. Buckley, R. Fernando, G. Hutchinson, G. Isbister, F. Konradsen, D. Murray, J. C. Piola, N. Senanayake, R. Sheriff, S. Singh, S. B. Siwach and L. Smit, Pesticide poisoning in the developing world—a minimum pesticides list, Lancet, 2002; 360: 1163-1167.
7 贺锡雯，吕京．有机磷类和拟除虫菊酯类农药的神经毒作用机理．中国药理学与毒理学杂志．1997；11(2)：89-90
8 Harputluoglu MM, Kantarceken B, Karincaoglu M, Aladag M, Yildiz R, Ates M, Yildirim B, Hilmioglu F. Acute pancreatitis: an obscure complication of organophosphate intoxication. Hum Exp Toxicol. 2003 Jun; 22(6): 341-3.
9 Akgur SA, Ozturk P, Solak I, Moral AR, Ege B. Human serum paraoxonase (PON1) activity in acute organophosphorous insecticide poisoning. Forensic Sci Int. 2003 Apr 23; 133(1-2): 136-40.
10 C. MacIlwain, Study proves Iraq used nerve gas, Nature 1993; 363: 3.
11 M. K. Johnson and P. Glynn, Neuropathy target esterase (NTE) and organophosphorus-induced delayed polyneuropathy (OPIDP): recent advances, Toxicol. Lett. 1995; 82/83. 459-463.
12 R. M. Black, J. M. Harrison and R. W. Read, The interaction of sarin and soman with plasma proteins: the identification of a novel phosphonylation site, Arch. Toxicol. 1999; 73: 123-126.
13 Jokanvoic M, Maksimovic M. Abnormal cholinesterase activity: understanding and interpretation [J]. Eur J clin chem. Clin biochem, 1997; 35(1): 11
14 Lotti M. Cholinesterase inhibition: complexities in interpretation [J]. Clin Chem, 1995, 41(12): 1814
15 张基美，黄金祥．常见农药毒性的几个问题[J)．中国工业医学志，1992，5(3)：160
16 沈伽弟．胆碱酯酶的基础与临床研究进展．军事医学科学院院刊，2000；24(4)：295-301：189-191
17 周艳，江新梅．有机磷农药中毒诊断的研究．医学综述，2004；10(3)
18 黄金祥．农药中毒国家诊断标准修订简介．职业卫生与应急救援．2003；21 (4)：175-176
19 陈嘉，周志俊等．乙酰胆碱酯酶研究进展对更新有机磷毒作用机理的认识．劳动医学，2001；18(1)：55-57
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2 T. C. Kwong, Organophosphate pesticides: biochemistry and clinical toxicology, Ther. Drug Monit. 2002; 24: 144-149.
3 M. Lotti, Clinical toxicology of anticholinesterase agents in humans. In: R. I. Krieger, Editor, Handbook of Pesticide Toxicology, Academic Press, San Diego 2001, 1043-1085.
4 D. Gunnell and M. Eddleston, Suicide by intentional ingestion of pesticides: a continuing tragedy in developing countries, Int. J. Epidemiol. 2003; 32: 902-909.
5 J. Cocker, H. J. Mason, S. J. Garfitt and K. Jones, Biological monitoring of exposure to organophosphate pesticides, Toxicol. Lett. 2002; 134: 97-103.
6 M. Eddleston, L. Karalliedde, N. Buckley, R. Fernando, G. Hutchinson, G. Isbister, F. Konradsen, D. Murray, J. C. Piola, N. Senanayake, R. Sheriff, S. Singh, S. B. Siwach and L. Smit, Pesticide poisoning in the developing world—a minimum pesticides list, Lancet, 2002; 360: 1163-1167.
7 贺锡雯，吕京．有机磷类和拟除虫菊酯类农药的神经毒作用机理．中国药理学与毒理学杂志．1997；11(2)：89-90
8 Harputluoglu MM, Kantarceken B, Karincaoglu M, Aladag M, Yildiz R, Ates M, Yildirim B, Hilmioglu F. Acute pancreatitis: an obscure complication of organophosphate intoxication. Hum Exp Toxicol. 2003 Jun; 22(6): 341-3.
9 Akgur SA, Ozturk P, Solak I, Moral AR, Ege B. Human serum paraoxonase (PON1) activity in acute organophosphorous insecticide poisoning. Forensic Sci Int. 2003 Apr 23; 133(1-2): 136-40.
10 C. MacIlwain, Study proves Iraq used nerve gas, Nature 1993; 363: 3.
11 M. K. Johnson and P. Glynn, Neuropathy target esterase (NTE) and organophosphorus-induced delayed polyneuropathy (OPIDP): recent advances, Toxicol. Lett. 1995; 82/83. 459-463.
12 R. M. Black, J. M. Harrison and R. W. Read, The interaction of sarin and soman with plasma proteins: the identification of a novel phosphonylation site, Arch. Toxicol. 1999; 73: 123-126.
13 Jokanvoic M, Maksimovic M. Abnormal cholinesterase activity: understanding and interpretation [J]. Eur J clin chem. Clin biochem, 1997; 35(1): 11
14 Lotti M. Cholinesterase inhibition: complexities in interpretation [J]. Clin Chem, 1995, 41(12): 1814
15 张基美，黄金祥．常见农药毒性的几个问题[J)．中国工业医学志，1992，5(3)：160
16 沈伽弟．胆碱酯酶的基础与临床研究进展．军事医学科学院院刊，2000；24(4)：295-301：189-191
17 周艳，江新梅．有机磷农药中毒诊断的研究．医学综述，2004；10(3)
18 黄金祥．农药中毒国家诊断标准修订简介．职业卫生与应急救援．2003；21 (4)：175-176
19 陈嘉，周志俊等．乙酰胆碱酯酶研究进展对更新有机磷毒作用机理的认识．劳动医学，2001；18(1)：55-57
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