Transcript L10

Organophosphate Inhibitors of AChE (4)

Enzyme inhibition by these agents can be reversed
by cholinesterase reactivators such as pralidoxime
if administered before “aging” of AChE has
occurred. Inhibition by agents that undergo rapid
“aging” is not reversed.

Except for echothiophate, these agents are
extremely lipid soluble, and some are very volatile.
Diisopropylflurophosphate (DFP) is a Substrate for AChE
The Extremely Slow Hydrolysis of Phosphorylated-AChE
New enzyme synthesis
is required for recovery
of enzyme function
Various “States” of Acetylcholinesterase
Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE
Acetylated-AChE Is Very Rapdily Hydrolyzed
AChE + Acetylcholine  AChE-acetylated + choline
AChE-acetylated + H2O  AChE + acetate
Hydrolysis of AChE-acetylated is rapid, in the order of
microseconds
P
Carbamylated-AChE Is Hydrolyzed Slowly
AChE + Carbamyl inhibitor  AChE-carbamylated +
noncarbamylated metabolite
AChE-carbamylated + H2O  AChE + carbamic acid
derivative
Hydrolysis of the AChE-carbamylated is slow, in the order of
hours. The carbamylated enzyme is reversibly inhibited, and
recovery of function is in the order of hours
Enzyme after phosphorylation by neostigmine
Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly
AChE + organophosphate inhibitor 
AChE-phosphorylated + nonphosphorylated metabolite
AChE-phosphorylated + H2O  AChE + phosphorylated
derivative
Hydrolysis of the AChE-phosphorylated is extremely slow, in
the order of days. The phosphorylated enzyme is
considered to be irreversibly inhibited, and recovery of
function is in the order of days. Pralidoxime, a reactivating
agent, may be adminstered to a subject before the enzyme
has “aged.”
Enzyme after phosphorylation by DFP
AGING OF ACETYLCHOLINESTERASE
Loss of An Alkyl Group From Phosphorylated
AChE “Ages” the Enzyme
AChE, phosphorylated
and inhibited by DFP
“Aged” AChE
“Aging” of Phosphorylated- AChE
Cholinesterase Reactivation