inactive compounds; however, insects do not have the hydrolases that would deactivate
the insecticide. Because of this double safety feature, the selectivity of malathion is
high and its mammalian toxicity low: the LD 50 for rats is 1500 mg/kg, p.o. The volatile
dichlorvos (8.22) is used in fly-killer strips. Whereas the vapors of this compound are
rapidly hydrolyzed by mammals, they are cumulative and highly toxic for insects.
Because of accidental exposure to insecticides by children or by agricultural workers,
an appreciation of the toxicities of insecticide anticholinesterase inhibitors is medically
relevant.
8.2.2.7 Acetylcholinesterase Inhibitors: Terrorism and Use as Nerve Gas Agents
Even longer-acting covalent AChE inhibitors are the organophosphate esters, such as
diisopropyl-phosphorofluoridate (8.23), developed from “nerve gases” discovered but
never used in World War II. These compounds are known for their extreme toxicity and
rapid dermal absorption. The covalently binding AChE inhibitors, and especially the
organophosphates, can be highly toxic, and poisoning from their improper use could
occur. An antidote, pralidoxime (8.24; 2-N-methylpyridinium-2-aldoxim iodide), was
designed on the basis of knowledge of their mode of action. The quaternary pyridinium
ion of this compound binds to the anionic site of the enzyme, removes the phosphate
of the inhibitor from the serine active site in the form of an oxime-phosphonate,
and regenerates AChE. Atropine (8.25) is also administered to victims of organophos-
phate poisoning to relieve peripheral and central muscarinic symptoms due to
excessive ACh.
ENDOGENOUS MACROMOLECULES 491