Neuropathic potential

B.W. Wilson, M. Hooper, E. Chow, R.J. Higgins, and J.B. Knaack, Antidotes and neuropathic potential of isofenphos. Bull. Environ. Contam Toxicol. 33 386, 1984. 

FIGURE 57.8. Spectrum of log values of relative inhibitory potency (RIP) = 7i(AChE)/ i(NTE), where = himolecular rate constant of inhibition. As log(RIP) becomes more positive, cholinergic potential increases as log(RIP) becomes more negative, delayed neuropathic potential increases. CPMO-chlorpyrifos methyl oxon. DCV derivatives refer to symmetrical dialkyl-2,2-dichlorovinyl phosphate (dichlorvos) compounds. EOPF - ethyl n-octylphosphonofluoridate. Data from Kropp and Richardson (2003) Richardson (1992) and Wu and Casida (1996). 

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. 

In a homologous series of OP compounds, increasing potency for AChE inhibition and cholinergic toxicity correlates with decreasing potency for NTE inhibition and OPIDN. The relative inhibitory potency (RIP) of an OP compound or its active metabolite for NTE versus AChE in vitro can be used as a convenient index of the probable neuropathic potential of the compound. A commonly used measure of inhibitory potency is the IC50, the concentration required to inhibit 50% of the enzyme activity under a standardized set of reaction conditions and time of incubation of the inhibitor with the enzyme preparation. A better measure of inhibitory potency is the bimolecular rate constant of inhibition, ki. When... 

This review describes characteristics of OPIDN, history of the problem, species and age sensitivity, role of NTE and structure of OP compounds in OPIDN initiation presents the last data on molecular properties NTE and its physilogical role a problem of OPIDN promotion is discussed. More fully the problem of OPIDN risk assessment will be considered, in particular, assessment of neuropathic potential of OP compounds including QSAR modelling, and biomonitoring of human exposure to neuropathic OP compounds based on biosensor NTE analysis in whole blood. The current state of OPIDN prevention and treatment will be presented. 

The results demonstrate the importance of both the phosphoryl moiety and its hydrophobicity as well as the features of the leaving group for OP neuropathic potential. 

Taking into account that inhibition of brain NTE and AChE are biomarkers for OPIDN and acute cholinergic toxicity, respectively [26,38], to evaluate the validity of in vitro predictions of the neuropathic potential of OP compounds, inhibition of NTE and AChE in hen brain was studied 24 h after im administration of increasing doses of methyl and butyl derivatives of PhP II compounds MePhP (RIP = 0.4) and BuPhP (RIP = 104.8) [62-64],... 

The correspondence between in vivo and in vitro predictions of neuropathic potential suggest that valid predictive QSAR models may be based on the in vitro approach. Adoption of this in vitro system would result in reducing experimental animal use, lowering costs, accelerating data production, and enabling standardization of a biochemically based risk assessment of the neuropathic potential of OP compounds. 

As noted above, the A(NTE)/ (AChE) ratio can be used as a convenient index of the probable neuropathic potential of the compound [3,26,40,55,57,58] We firstly used a QSAR approach for quantitative analysis structure - NTE selectivity and obtained equations describing dependence of neuropathic potential of O-phosphorylated oximes I-IV on the hydrophobicity and steric properties of the studied compounds. 

Substituting the specific values for the coefficients in Eq. 10 gives (E7i)opt= 2.48 for phenyl phosphonates II, that corresponds to the compound with the maximum neuropathic potential in this series, that is pentyl derivative (E7i=2.5). For methylphosphonates I (Z7i)opt = 2.22, that corresponds to isopentyl derivative (l7i=2.3). For dialkylphosphates III (l7i),1 il= 4.02, and dibutylphosphate (l7i=4.0) has the maximum neuropathic potential in this series. 

Makhaeva, G.F., Malygin, V. V., and Martynov, I. V. Assessment of neuropathic potential of some methyl- and phenylphosphonates using a stable preparation of neuropathy target esterase from chicken brain, Doklady Biochem. Biophys., 377,68-71,2001. 

Makhaeva, G.R, Rudakova, E.V., Hein, N.D., et al., 2014. Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds. J. Appl. Toxicol, doi http //dx.doi.org/10.1002/ jat.2977. 

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