Mipafox

The rapid growth in the use of OPs and the proliferation of new active ingredients and formulations was not without its problems. Some OPs proved to be too hazardous to operators because of very high acute toxicity. A few were found to cause delayed neurotoxicity, a condition not caused by ChE inhibition (e.g., mipafox, lepto-phos). There was also the problem of the development of resistance, for example, by... 

Certain OP compounds including DFP, mipafox, and leptophos Organomercury and organolead compounds... 

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). 

Neuropathy target esterase (NTE) An esterase of the nervous system whose inhibition by certain OPs (e.g., mipafox, leptophos) can lead to the development of delayed neuropathy. 

Two chemists investigating the insecticidal properties of Mipafox developed weakness and unsteady gait about two to three weeks after their recovery from an acute poisoning episode. This progressed to bilateral foot drop in one victim, who ultimately did recover. The other was less fortunate, progressing to a persistent and flaccid paralysis of his lower extremities, with no improvement after two years (ref. 167). 

Occupational Exposure during the Manufacture and Formulation of Pesticides. PHEW (NIOSH) No. 78-174 US-GP0, Washington, DC (1978), 429 pp., 343 refs., 5 appendices. Bidstrup, P., J.A. Bonnell and A. Beckett, "Paralysis following Poisoning by a New Organic Phosphorus Insecticide (Mipafox)", Brit. Med. J.(l) 1068-1072 (1953). As cited in ref. 164. 

Neurotoxic chemicals and motor neuropathy Chlorpyrifos, dichlorvos (DDVP), EPN, n-hexane, 2-hexanone, lead, lead chromate, lead II thiocyanate, leptophos, methamidophos, mipafox, omethoate, parathion, trichlor-fon, trichloronate, triorthocresyl phosphate Neurotoxic chemicals and sensorimotor neuropathy acrylamide, allyl chloride, arsenic and compounds, arsenic trichloride, calcium arsenate, carbon disulfide, dichloroacetylene, ethylene oxide, gallium arsenide, lead arsenate, mercuric chloride, mercuric nitrate, mercurous nitrate, mercury, nitrous oxide, phenyl arsine oxide, thallium and soluble compounds, thallous nitrate... 

NTE was first identified as the presumptive target of neuropathic OP compounds in the initiation of OPIDN (Johnson, 1970). Its activity in cells and tissues is operationally defined as the enzymatic hydrolysis of the non-physiological substrate, phenyl valerate, which is resistant to inhibition by diethyl 4-nitrophenyl phosphate (paraoxon) and sensitive to inhibition by A.A -diisopropylphosphor-odiamidic fluoride (mipafox) under specified conditions of preincubation with inhibitors and subsequent incubation with substrate (Johnson, 1977 Kayyali et al., 1991 Makhaeva et al., 2007). 

In contrast to the results for mipafox-inhibited NTE, early limited studies indicated that mipafox-inhibited BChE or AChE undergo irreversible aging, because the enzymes could be reactivated soon after inhibition, but not after 18 h (Milatovic and Johnson, 1993). The chemistry of phosphoramidates suggest that aging could involve hydrolytic loss of an alkylamino group. For example, acid-catalyzed P-N bond fission has been observed for certain A-alkyl phosphoramidates (Eto, 1974) and the aging of tabun-inhibited AChE has been shown to proceed via P-N bond scission with loss of dimethylamine (Elhanany et ah, 2001). 

Kropp, T.J., Richardson, R.J. (2003). Relative inhibitory potencies of chlorpyrifos oxon, chlorpyrifos methyl oxon, and mipafox for acetylcholinesterase versus neuropathy target esterase. J. Toxicol. Environ. Health Part A 66 1145-57. 

Kropp, T.J., Glynn, P., Richardson, R.J. (2004). The mipafox-inhibited catal 4ic domain of human neuropathy target esterase ages by reversible proton loss. Biochemistry 43 ... 

Toxicity of organophosphates can be potentiated 15-20-fold in rats and mice by pretreatment with a metabolite of tri-O-cresylphosphate, CBDP (2-0-cresyl)-4H-l,3,2-benzodioxa-phosphorin-2-oxide), which is an irreversible inhibitor of CarbEs. In similar studies, tetraisopropylpyrophosphoramide (iso-OMPA), or mipafox, an organophosphate-irreversible inhibitor of CarbEs, potentiates three-to fivefold the toxicity of several OPs (soman, DFP, and methylparathion) and carbamates (carbofuran, aldicarb, propoxur, and carbaryl). Inhibition of CarbEs by CBDP, iso-OMPA, or mipafox pretreatment, particularly in plasma, liver, heart, brain, and skeletal muscles, is a major contributory factor in the potentiation of toxicity of organophosphates and carbamates. Thus, the toxicity of any drug, pesticide, or other type of agent that is normally detoxified by CarbEs, could be potentiated by pre-exposure to an organophosphorus or other carboxylesterase inhibitor. 

Fluorophosphates are also highly toxic and relatively volatile. Sarin and soman are chemical warfare agents. Diisopropyl fluorophosphate (DFP) is often used by biochemists to study serine-active enzymes. Mipafox and DFP cause OPIDN in humans and experimental animals. 

Mipafox Fisons Pest Control Ltd. Bis- (isopropylamino) -phosphorylfluorid 83> LD 50 25—50 mg/kg Ratte... 

Structures of several common substrates and an inhibitor used to study the mechanisms of OPA anhydrase activity. DFP (diisopropylfluorophosphate), mipafox (N,N -diisopropylphosphorodi-amidofluoridate), tabun (N,N-dimethylethylphosphoroamidocyanidate), soman(0-l,2,2-trimethylpropylmethylphosphonofluoridate, paraoxon (diethyl 4-nitrophenyl phosphate), and parathion. 

Characteristic Activity mw1 Soman/ DFP Ratio Mn2+ Stimulation Mipafox Inhibition... 

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