ABSTRACT
This paper provides new information related to the mechanism of OPI (organophosphorus insecticides) teratogenesis. The COMFA (comparative molecular field analysis) and COMSIA (comparative molecular similarity indices analysis) suggest that the electrostatic and steric fields are the best predictors of OPI structural requirements to inhibit in ovo chicken embryo yolk sac membrane kynurenine formamidase, the proposed target for OPI teratogens. The dominant electrostatic interactions are localized at nitrogen-1, nitrogen-3, nitrogen of 2-amino substituent of the pyrimidinyl of pyrimidinyl phosphorothioates, and the oxygen of crotonamide carbonyl in crotonamide phosphates. Bulkiness of the substituents at carbon-2 and carbon-6 of the pyrimidinyls and/or N-substituents and carbon-3 substituents of crotonamides are the steric structural components that contribute to superiority of those OPI as in ovo inhibitors of kynurenine formamidase.
Subject(s)
Arylformamidase/antagonists & inhibitors , Insecticides/chemistry , Insecticides/toxicity , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/toxicity , Quantitative Structure-Activity Relationship , Teratogens/toxicity , Yolk Sac/enzymology , Animals , Chick Embryo , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/toxicity , Leptophos/chemistry , Leptophos/toxicity , Models, Molecular , Parathion/chemistry , Parathion/toxicity , Static Electricity , Teratogens/chemistry , Yolk Sac/drug effectsABSTRACT
We have evaluated in vitro the potency of 23 oximes to reactivate human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) inhibited by racemic leptophos-oxon (O-[4-bromo-2,5-dichlorophenyl]-O-methyl phenyl-phosphonate), a toxic metabolite of the pesticide leptophos. Compounds were assayed in concentrations of 10 and 100 µM. In case of leptophos-oxon inhibited AChE, the best reactivation potency was achieved with methoxime, trimedoxime, obidoxime and oxime K027. The most potent reactivators of inhibited BChE were K033, obidoxime, K117, bis-3-PA, K075, K074 and K127. The reactivation efficacy of tested oximes was lower in case of leptophos-oxon inhibited BChE.
Subject(s)
Acetylcholinesterase/chemistry , Butyrylcholinesterase/chemistry , Leptophos/analogs & derivatives , Oximes/chemistry , Pesticides/chemistry , Erythrocytes/drug effects , Erythrocytes/enzymology , Humans , Leptophos/chemistry , Leptophos/pharmacology , Pesticides/pharmacologyABSTRACT
Enantiomers of leptophos were separated by high-performance liquid chromatography with a Whelk-O1 column using 3% dichloromethane in n-hexane as mobile phase. Toxicity tests of leptophos enantiomers and racemate were performed with daphnia. Enzyme inhibition of leptohpos was carried out by using butyryl cholinesterase from horse serum and acetylcholinesterase from housefly heads. From the inhibition test of butyrylcholinesterase, the half-inhibitory concentrations, IC(50), of (+)-leptophos, (-)-leptophos, and (+/-)-leptophos were 0.241, 1.17, and 1.05 gmL(-1), respectively. No significant difference in IC(50) in (-)-leptophos and (+/-)- leptophos was found. However, the IC(50) of (+)-leptophos was significantly different from those of the others. In the inhibition test of acetylcholinesterase, the IC(50) values of (+)-leptophos, (-)-leptophos, and (+/-)-leptophos were 14.01, 24.32, and 13.22 gmL(-1), respectively. There was no significant difference in IC(50) in (+)-leptophos and (+/-)-leptophos, although the IC(50) of (-)-leptophos was significantly different from those of the others. From these results, leptophos-both enantiomers and racemate-seems to have higher neurotoxicity for mammals than for the target insects. In the toxicity test of daphnia, the half-lethal concentrations, LC(50), of (+)-leptophos, (-)-leptophos, and (+/-)-leptophos were 0.0387, 0.802, and 0.0409 gL(-1), respectively. There is no significant difference in LC(50) in (+)-leptophos and (+/-)-leptophos. The LC(50) of (-)-leptophos is significantly higher than those of the others. From these results, (-)-leptophos has lower toxicity to daphnia.
