Neuropathy target esterase inhibition

Davis, S.L., Tanaka, D., Jr., Aulerich, R.J., Bursian, S.J. (1999). Organophosphorus-induced neurotoxicity in the absence of neuropathy target esterase inhibition the effects of triphenyl phosphine in the European ferret. Toxicol. Sci. 49 78-85. 

Ehrich M, Correll L, Veronesi B. Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. Fund Appl Toxicol. 1997 38 55-63. 

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. 

A third enzyme may have limited potential as a measure of exposure. Neurotoxic esterase, also known as neuropathy target esterase (NTE), is inhibited by certain organophosphate esters. When brain NTE is inhibited above 70% for acute or possibly as low as 50% for repeated exposures, there is a consensus that delayed neuropathy is likely. NTE also is found in lymphocytes and platelets (Lotti et al. 1984). The... 

Some OP compounds induce delayed neurotoxic effects ("delayed neuropathy") after acute poisoning. This delayed neurotoxic action is independent of cholinesterase inhibition but related to phosphorylation of a specific esterasic enzyme in the nervous tissue, called "neurotoxic esterase" or "neuropathy target esterase" (NTE) (Johnson, 1982). NTE is present in the nervous tissue, liver lymphocytes, platelets, and other tissues, but its physiological function is unknown. There is a rather large inter-individual variation of lymphocyte and platelet NTE activity (Table 2). 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

OPs are known to induce time-delayed neurotoxicity. This is due to the inhibition of an esterase in nerve tissue, neuropathy target esterase (NTE), that is also found in muscle and blood cells. The NTE level in the blood is an indicator of the inhibition of the enzyme. Inhibition of NTE and aging, the process of following the OP binding to an active esterase site that prevents the reactivation of the site, is important for selection of an antidote against certain OP nerve agents. It is of primary concern for Novichok agent. There is little information available on OP-caused neurotoxicity and the cardiac toxicity. 

Barril, J., Estevez, J., Escudero, M.A., Cespedes, M.V., Niguez, N., Sogorb, M.A., Monroy, A., Vilanova, E. (1999). Peripheral nerve soluble esterases are spontaneously reactivated after inhibition by paraoxon implications for a new definition of neuropathy target esterase. Chem. Biol. Interact. 119-20 541-50. 

Tri-ort/io-cresyl phosphate, the contaminant in a homemade liquor called Ginger Jake , which is responsible for delayed neuropathy and paralysis of the legs, is bioactivated to a form that inhibits neuropathy target esterase but not acetylcholinesterase (Casida and Quistad, 2004 Glynn, 2006). Large structures with a 12-20 carbon alkyl chain on the phosphorus atom inhibit fatty acid amide hydrolase but not acetylcholinesterase (Casida and Quistad, 2004). These examples clearly show that OPs which do not affect... 

FIGURE 57.5. Subclasses of neuropathy target esterase (NTE) inhibitors. Type A inhibitors include phosphates, phosphonates, and phosphoramidates these are neuropathic and capable of aging. T pe B inhibitors include phosphinates, sulfonates, and carbamates these are nonneuropathic and not capable of aging. However, inhibition of NTE with a type B inhibitor will protect against organophosphorus compound-induced delayed neurotoxicity (OPIDN) from subsequently administered type A inhibitors. Reproduced with permission from Richardson (2005). 

FIGURE 57.9. Inhibition and aging of serine esterases by diisopropylphosphorofluoridate (DFP). The active site serine is organophosphorylated in the inhibition step. Aging results in net loss of an isopropyl group to yield the monoisopropylphosphoryl esterase. This mode of inhibition and aging has been established for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and neuropathy target esterase catalytic domain (NEST) (Kropp and Richardson, 2007). 

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 ... 

Lotti, M., Moretto, A., Zoppellari, R., Dainese, R., Rizzuto, N., Barusco, G. (1986). Inhibition of lymphocytic neuropathy target esterase predicts the development of organophosphate-induced delayed polyneuropathy. Arch. Toxicol. 59 176-9. 

Milatovic, D., Johnson, M.K. (1993). Reactivation of phosphor-amidated acetylcholinesterase and neuropathy target esterase hy treatment of inhibited enzyme with potassium fluoride. Chem. Biol. Interact. 87 425-30. 

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