Diisopropyl-phosphofluoridate

A few OP compounds cause delayed neuropathy in vertebrates because they inhibit another esterase located in the nervous system, which has been termed neuropathy target esterase (NTE). This enzyme is described in Chapter 10, Section 10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate (DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay in the appearance of neurotoxic symptoms following exposure is associated with the aging process. In most cases, nerve degeneration is not seen with initial inhibition of the esterase but appears some 2-3 weeks after commencement of exposure, as the inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as OP-induced delayed neuropathy (OPIDN). 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

Bouma BN, Miles LA, Beretta G et al (1980) Fluman plasma prekallikrein. Studies of its activation by activated factor XII and of its inactivation by diisopropyl phosphofluoridate. Biochemistry 19 1151-1160... 

SYNS DFP DIFLUPYL DIFLUROPHATE DIISOPROPOXYPHOSPHORYL FLUORIDE DIISOPROPYL FLUOROPHOSPHATE 0,0-DIISOPROPYL FLUOROPHOSPHATE DIISOPROPYL FLUOROPHOSPHONATE DIISOPROP i LFLUORO-PHOSPHORIC ACID ESTER DIISOPROPYLFLUOR-PHOSPHORSAEUREESTER (GER.VIAN) DIISOPROPYL PHOSPHOFLUORIDATE DIISOPROPYL PHOSPHOROFLUORIDATE 0,0 -DIIS0PR0PYL PHOSP-HORYL FLUORIDE DYFLOS FLOROPRYL FLUOPHOSPHORIC ACID, DIISOPROPYL ESTER FLUORODIISOPROPYL PHOSPHATE FLUOROPRYL... 

Gustafson RL, Chaberek S and Martell AE (1963). A kinetic study of the cipper (n) chelate catalyzed hydrolysis of diisopropyl phosphofluoridate. J Am... 

Clothier, B. and Johnson, M.K., Rapid aging of neurotoxic esterase after inhibition by diisopropyl phosphofluoridate, Biochem. J., Ill, 549, 1979. 

Fig. 8.17 A. Acetylcholinesterase normally catalyzes inactivation of the neurotransmitter acetylcholine in a hydrolysis reaction. The active site serine forms a covalent intermediate with a portion of the substrate during the course of the reaction. B. Diisopropyl phosphofluoridate (DFP), the ancestor of current organophosphorus nerve gases and pesticides, inactivates acetylchohnesterase by forming a covalent complex with the active site serine that cannot be hydrolysed by water. The result is that the enzyme cannot carry out its normal reaction, and acetylcholine accumulates.

Little JS, Broomfield CA, Fox-Talbot MK, Boucher LJ, Maclver B, Lenz DE. Partial characterization of an enzyme that hydrolyzes sarin, soman, tabun, and diisopropyl phosphofluoridate (DFP). Biochem Pharmacol. 1989 38 23-29. 

Organophosphorus reagents that inhibit hydrolases (serine hydrolases) diethyl p-nitrophenyl phosphate (paraoxon) diisopropyl phosphofluoridate (DFP) dimethyl(dichlorovinyl) phosphate (dichlovos) O -methylphosphoramidothioate 3-hydroxy-N-methyl-cis-crotonamide dimethylphosphate tetraethyl pyrophosphate (TEPP)... 

The protease/esterase inhibitor diisopropyl phosphofluoridate (LFP) was shown to block the cleavage of poliovirus polyprotein (7) This implicates a protease with a serine-containing active site. 

Large amounts of 0-isopropyl methylphosphonic acid were found in blood and nrine of victims of the terrorist attacks with sarin in Matsumoto and Tokyo. Until recently, it was assnmed that hydrolysis of phosphofluoridates in plasma and tissues of mammals proceeds exclusively by cleavage of the P F bond. For example, treatment of C( )P( )- P-soman with rat plasma or liver homogenate did not lead to any conversion of PMPA into the secondary hydrolysis product methylphosphonic acid (MPA). Ramachandran observed that the primary hydrolysis product of DF P, i.e., 0,0-diisopropyl P-phosphoric acid, is not metabolized after s.c. admiiustration to mice. Rather, the product was excreted unchanged into urine. However, Nakajima et al. reported that MPA was detected (in urine) until the third day after hospitalization of a victim of the terrorist attack with sarin in Matsumoto. This discrepancy needs further investigation. 

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