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QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS PREDICT THE DELAYED NEUROTOXICITY POTENTIAL OF A SERIES OF O-ALKYL-O-METHYLCHLOROFORMIMINO PHENYLPHOSPHONATES.

Authors :
Malygin, Vladimir
Sokolov, Vladimir
Richardson, Rudy
Makhaeva, Galina
Source :
Journal of Toxicology & Environmental Health: Part A. 2003, Vol. 66 Issue 7, p611-625. 15p.
Publication Year :
2003

Abstract

Inhibition of acetylcholinesterase (AChE) versus inhibition and aging of neuropathy target esterase (NTE) by organophosphorus (OP) compounds in vivo can give rise to distinct neurological consequences: acute cholinergic toxicity versus OP compound-induced delayed neurotoxicity (OPIDN). Previous work has shown that the relative potency of an OP compound to react with NTE versus AChE in vitro may predict its capability to produce OPIDN. The present study was conducted to evaluate further the validity of such predictions and to enhance them with quantitative structure-activity relationships (QSAR) using a homologous series of alkyl phenylphosphonates, (RO)C 6 H 5 P(O)ON=CClCH 3 (PhP; R=alkyl). Neuropathic potential of PhP was assessed by measuring k i (NTE)/k i (AChE) ratios in vitro and comparing these with ED50 ratios in vivo. Selectivity for NTE increased with rising R-group hydrophobicity. The k i (NTE)/k i (AChE) ratios were 0.42 (methyl), 3.6 (ethyl), 15 (isopropyl), 36 (propyl), 69 (isobutyl), 105 (butyl), and 124 (pentyl). Ratios >1 suggest the potential to produce OPIDN at doses lower than the LD50. Inhibition of NTE and AChE in hen brain in vivo was studied 24 h after im injection of hens with increasing doses of methyl and butyl derivatives. Analysis of dose-response curves yielded ED50(AChE)/ED50(NTE) ratios of 0.86 for methyl PhP and 22.1 for butyl PhP. These results predict that the butyl derivative should be more neuropathic than the methyl analogue. Excellent correspondence between in vivo and in vitro predictions of neuropathic potential indicate that valid predictive QSAR models may be based on the in vitro approach. Adoption of this 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15287394
Volume :
66
Issue :
7
Database :
Academic Search Index
Journal :
Journal of Toxicology & Environmental Health: Part A
Publication Type :
Academic Journal
Accession number :
9473740
Full Text :
https://doi.org/10.1080/15287390306374