Neuropathy target esterase aging

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). 

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. 

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). 

Johnson, M.K., Read, D.J. (1987). The influence of chirality on the delayed neuropathic potential of some organophosphoms esters neuropathic and prophylactic effects of stereoisomeric esters of ethyl phenylphosphonic acid (EPN oxon and EPN) correlate with quantities of aged and imaged neuropathy target esterase in vivo. Toxicol. Appl. Pharmacol. 90 103-15. 

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 ... 

Jokanovic, M., Stepanovic, R.M., Maksimovic, M., Kosanovic, M., Stojiljkovic, M.P. (1998). Modification of the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase of hen brain. Toxicol. Lett. 95 93-101. 

The complete mechanism of OPIDN has not been elucidated. However, there is good evidence that the disease is initiated by a concerted two-step reaction involving inhibition and aging of a critical amount of a protein called neuropathy target esterase (neurotoxic esterase, NTE) in target neural tissues. The net result of the aging step is the rapid formation of a... 

Singh, A.K. QSAR for the organophosphate-induced inhibition and aging of the enzyme neuropathy target esterase (NTE), SAR QSAR Environ. Res., 12,275-295,2001. 

Sogorb, M.A., Gonz lez-Gonz lez, L, Pamies, D., et al., 2010. An alternative in vitro method for detecting neuropathic compounds based on acetylcholinesterase inhibition and on inhibition and aging of neuropathy target esterase (NTE). Toxicol. In Vitro 24 (3), 942-952. 

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