Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical Warfarement time of about 50 days. Its activity is decreasedin parenchymal liver disease, acute infections, malnutrition,and chronic debilitating diseases, and isincreased in the nephrotic syndrome. 22 This enzymehas no known physiological function in blood, butmay assist in hydrolyzing certain choline esters.People who have a prolonged paralysis causedby succinylcholine, a muscle relaxant, usually havelow BuChE activity. 22 The structure of BuChE is determinedby two autosomal alleles. The frequency ofoccurrence of the gene responsible for abnormal ChEis about 1 in 2,000 to 1 in 4,000 people. Thus, about96% of the population have the usual phenotype, closeto 4% have the heterozygous phenotype, and about0.03% have the homozygous abnormal phenotype. 22 Inaddition to having the low BuChE activity in the usualassay (as a result of this genetic abnormality), peoplewith abnormal ChE have low dibucaine numbers (theenzyme activity in an assay in which dibucaine is usedas the ChE substrate). The mean dibucaine numberfor the normal phenotype is about 79%, that for theheterozygote is 62%, and that for the homozygousabnormal phenotype is 16%. 26 There are over 20 variantsof the abnormal BuChE phenotype, each withdifferent, low dibucaine numbers, including zero.The relationship of BuChE activity and succinylcholinecan be somewhat different. One author 27reports on an individual whose BuChE activity was3 times higher than normal. His dibucaine numberwas normal, and he was found to be relatively resistantto succinylcholine. His sister and daughter alsohad high BuChE activities. The author of this reportsuggests that this abnormality is autosomal dominantand that it represents another genetic abnormalityof BuChE.Erythrocyte CholinesteraseRBC-ChE is synthesized with the erythrocyte,which has an average life of 120 days. The activity ofthis enzyme is decreased in certain diseases involvingerythrocytes, such as pernicious anemia, and isincreased during periods of active reticulocytosis, suchas recovery from pernicious anemia, because reticulocyteshave higher ChE activity than do mature cells.No other disease states are known to affect RBC-ChEactivity, 22 but one report 28 describes three members ofone family who had decreased RBC-ChE activity, suggestingthat differences in this enzyme are genetic.The physiological role of the enzyme in (or on thestroma of) the erythrocyte is unknown. Recovery ofRBC-ChE activity after irreversible inhibition takesplace only with the synthesis of new erythrocytes, orat a rate of approximately 1% per day.Variation in Cholinesterase ActivitiesButyrylcholinesteraseIn longitudinal studies 29,30 lasting 3 to 250 weeks,the coefficient of variation (standard deviation dividedby the mean) for an individual ’ s BuChE activityranged from 5% to 11.8% in both men and women. Ofthe ranges (the difference between the highest andlowest activities divided by the mean) for individualsin the study, the lowest was 24% and the highest was50% over 1 year. 30BuChE activity does not vary with age in women 31,32until the age of 60 years, when higher BuChE activitiesare seen. 32 BuChE activities in men have been reportedin some studies to increase with age and in otherstudies to decrease with age. 20 In matched age groups,BuChE activity was higher in men than in women, 20,30and higher in women not taking oral contraceptivesthan in those taking them. 32–34Erythrocyte CholinesteraseRBC-ChE activity is more stable than the activityof the BuChE. 30,35,36 In a study 30 that lasted 1 year, thecoefficients of variation were 2.1% to 3.5% in men and3.1% to 4.1% in women, with ranges of 7.9% to 11.4%in men and 12.0% to 15.9% in women. This variationwas less than that observed for the hematocrits ofthese individuals.It is unclear whether age affects RBC-ChE activity.In one study, 31 RBC-ChE activity was unchanged withage, while in another, 32 enzyme activity increasedwith age from the third to the sixth decades in men,with a less marked increase through the fifth decadein women.Inhibition of Blood CholinesterasesSome ChE-inhibiting substances inhibit BuChEpreferentially, and some inhibit RBC-ChE preferentially.Large amounts of ChE inhibitors will completelyinhibit both enzymes.The blood enzymes appear to act as effectivescavengers of nerve agents while they remain in thecirculation. There is little inhibition of tissue enzymeuntil much of the blood enzyme is inhibited because,with the exception of local tissue effects (eg, eye,respiratory tract, skin contact), the blood is the firsttissue to encounter the agent. The RBC-ChE appearsto correlate more closely with tissue ChE and physiologicalsigns of poisoning than the plasma enzymein this regard. In two studies, 37,38 a small dose of DFPin humans inhibited about 90% of the plasma enzyme164