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Cohen SD, Williams RA, Killinger JM, Freudenthal RI: Comparative sensitivity of bovine and rodent acetylcholinesterase to in vitro inhibition by organophosphate insecticides. Toxicol Appl Pharmacol. 1985 Dec;81(3 Pt 1):452-9.
Biochemical studies were conducted to compare the in vitro sensitivities of bovine and rodent brain and erythrocyte cholinesterases to inhibition by Dyfonate-oxon, paraoxon, and malaoxon. This comparison was done to determine if the reported greater sensitivity of cattle to Dyfonate might be explained by a greater sensitivity of the target enzyme, acetylcholinesterase, in cattle to inhibition by Dyfonate's toxic metabolite, Dyfonate-oxon. Studies were conducted with brain homogenates and lysed erythrocytes obtained from cows and from male and female rats. Additional studies were conducted with a commercially available sample of purified bovine erythrocyte acetylcholinesterase (ACHE). In all cases, the concentrations of organophosphates required to produce 50% inhibition (IC50) of enzyme activity were determined. Cow brain ACHE was 1.7 to 3.8 times more resistant to inhibition by Dyfonate-oxon, paraoxon, and malaoxon than was brain ACHE from male or female rats. For both species, paraoxon was 1.2 to 1.6 times more potent than Dyfonate-oxon and 3.8 to 6.9 times more potent than malaoxon. The bimolecular reaction rate constants (ki) were also determined for inhibition of brain ACHE of cows and male rats by the three organophosphates. In general, the ki data were in agreement with the IC50 data indicating that cow brain ACHE was less sensitive than rat brain ACHE to inhibition. Additional IC50 studies were conducted with lysed erythrocytes from cows and from male and female rats. Both quantitative and qualitative differences between species and among the organophosphates were in excellent agreement with the results of the brain ACHE studies. Also, in related studies with purified bovine erythrocyte ACHE, there was excellent agreement with the results of tests involving ACHE inhibition in erythrocyte lysates. This study demonstrated that, as an inhibitor of ACHE in vitro, Dyfonate-oxon was equal to or slightly lower in potency than paraoxon and more potent than malaoxon. In addition, the study demonstrated that, in general, ACHE from brain or erythrocytes of cows was less sensitive to in vitro inhibition by organophosphates than was that from male or female rats. Thus, the apparent greater susceptibility of cows to Dyfonate, in vivo, cannot be explained on the basis of an unusual target enzyme (ACHE) sensitivity to inhibition by Dyfonate-oxon. |
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