Isoflurophate acetylcholinesterase

Mechanism of action Isoflurophate [eye soe FLURE oh fate] (diisopropylfluorophosphate, DFP) is an organophosphate that covalently binds to a serine-OH at the active site of acetylcholinesterase (Figure 4.9). Once this occurs, the enzyme is permanently inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules. Following covalent modification of acetylcholinesterase, the phosphorylated enzyme slowly releases one of its isopropyl groups (Figure 4.9). The loss of an alkyl group, which is called... 

Therapeutic uses An ophthalmic ointment of the drug is used topically in the eye for the chronic treatment of open-angle glaucoma. The effects may last for up to one week after a single administration. [Note Echothiophate [ek oe THI oh fate] is a newer drug that covalently bonds to acetylcholinesterase. Its use is the same as isoflurophate.]... 

Covalent modification of acetylcholinesterase by isoflurophate also shown is the reactivation of the enzyme with pralidoxime. 

Correct answer = O. Bradycardia (rather than tachycardia) and decreased cardiac output result from increased parasympathetic stimulation. Since isoflurophate inhibits acetylcholinesterase and increases the concentration of acetylcholine at the synapse, it mimics (parasympathetic) stimulation. 

Because the ACh receptor does not hydrolyse acetylcholine, the esteratic site of acetylcholinesterase (see Fig. 12.3) must be absent. Other fundamental differences in the two sites are indicated by the following (a) dimethylbutyl acetate 12.66) is a good substrate for the enzyme, but barely activates the receptor which requires a basic group for marked activity (b) muscarine is not a substrate for the enzyme and yet it is a powerful agonist for the muscarinic receptor (c) di-isopropyl phosphorofluoridate (isoflurophate) 13.26) binds to the active site of AChase but not to an ACh receptor (d) acetyl-bungarotoxin specifically binds to the ACh nicotinic receptor but not to the enzyme. 

Michalek, H., Meneguz, A., Bisso, G.M., 1982. Mechanisms of recovery of brain acetylcholinesterase in rats during chronic intoxication by isoflurophate. Arch. Toxicol. Suppl. 5,116-119. 

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