A comparison of the decarbamoylation rates of physostigmine-inhibited plasma and red cell cholinesterases of man with other species.
Plasma and red cells from a variety of animal species were used to demonstrate that there is a relationship between the decarbamoylation rates of physostigmine-inhibited plasma and red cell cholinesterases in vitro and the effectiveness of carbamate pretreatment against nerve agent poisoning reported in the literature. Decarbamoylation rates were faster in the non-human primates than in the guinea-pig, and carbamate pretreatment is more effective in these species than in the guinea-pig. The data for the decarbamoylation rates of physostigmine-inhibited enzymes suggests that the non-human primates are the best animal model for extrapolation of protection studies from animal species to man. Control values for red cell acetylcholinesterase (AChE) activity (mumol/min/mL blood) using acetylthiocholine (1 mM) were higher in the human (4.98) and the rhesus monkey (4.14) than in the marmoset (0.84) and the guinea-pig (0.83). Plasma cholinesterase (ChE) activity (mumol/min/mL plasma) using butyrylthiocholine (10 mM) was highest in the rhesus monkey (9.29), intermediate in human (5.10) and guinea-pig (6.06), and lowest in the marmoset (4.07). There was a species difference in the relative activity of AChE: ChE in blood, human (65:35), rhesus monkey (45:55), marmoset (30:70) and guinea-pig (20:80). The rate of recovery of red cell AChE and plasma ChE activities, following incubation of whole blood with physostigmine (1 x 10(-7) M), was in the order human greater than rhesus monkey greater than marmoset greater than guinea-pig. During the incubation of red cells with physostigmine there was little recovery of AChE activity for 3-4 hr in any species. During the incubation of plasma with physostigmine there was complete recovery of ChE activity by 2-3 hr in the human and rhesus monkey and a significant recovery by 3 hr in the marmoset and guinea-pig. This suggests that a component of plasma, possibly ChE, was responsible for the degradation of physostigmine, presumably by hydrolysis. There was a marked species difference in the decarbamoylation rates of physostigmine-inhibited enzyme. In the red cell the t1/2 values (min) were 14.8 (human), 21.2 (rhesus monkey), 17.9 (marmoset) and 31.9 (guinea-pig). In the plasma the t1/2 values (min) were 11.2 (human), 32.9 (rhesus monkey), 44.1 (marmoset) and 52.4 (guinea-pig).
Wetherell
J R
JR
Biology Division, Chemical Defence Establishment, Salisbury, Wiltshire, U.K.
French
M C
MC
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002143:Callitrichinae; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism*; D004911:Erythrocyte Volume; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D010830:Physostigmine / Q000493:pharmacokinetics / Q000494:pharmacology*; D010949:Plasma / Q000187:drug effects; D010950:Plasma Cells / Q000187:drug effects* / Q000201:enzymology; D011041:Poisoning / Q000517:prevention & control; D012999:Soman / Q000506:poisoning; D013045:Species Specificity; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D012999:Soman; D010830:Physostigmine; D000110:Acetylcholinesterase; D002802:Cholinesterases