Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: Sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

Abstract

Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC 50 values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes and brain remain to be defined.

Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids

“…The relationship between NTE and lysophospholipases is of particular interest since they both hydrolyze LysoPC and similar OP inhibitor profiles are obtained with mouse brain NTE and LysoPC hydrolase assays [29] and recombinant NTE (rNTE) (Vose, unpublished results); surprisingly this extends to human erythrocyte and lymphocyte LysoPC hydrolases [38] (Fig. 5).…”

“…NTE and LysoPLA I may have a similar function but they are very different in structure. LysoPLA I has the canonical alpha/beta hydrolase fold and a catalytic Ser-Asp-His triad [38]. Because blood LysoPC hydrolase activity is similar to rNTE in OP inhibitor sensitivity and specificity, the blood enzymes were evaluated for possible biomonitoring of exposure to OP pesticides and neurotoxicants using mice as the model.…”

“…Because blood LysoPC hydrolase activity is similar to rNTE in OP inhibitor sensitivity and specificity, the blood enzymes were evaluated for possible biomonitoring of exposure to OP pesticides and neurotoxicants using mice as the model. Mice treated with the highest tolerated doses of widely-used OP insecticides showed only moderate reductions in blood LysoPC hydrolase activity, indicating that this is not an appropriate marker for OP pesticide exposure [38]. However, EOPF gives dose-dependent reduction in brain NTE and blood LysoPC hydrolase activities [38].…”

“…Mice treated with the highest tolerated doses of widely-used OP insecticides showed only moderate reductions in blood LysoPC hydrolase activity, indicating that this is not an appropriate marker for OP pesticide exposure [38]. However, EOPF gives dose-dependent reduction in brain NTE and blood LysoPC hydrolase activities [38]. For this compound, lysoPC hydrolase inhibition in blood is as good as that in brain to predict delayed neurotoxicity [38].…”

“…However, EOPF gives dose-dependent reduction in brain NTE and blood LysoPC hydrolase activities [38]. For this compound, lysoPC hydrolase inhibition in blood is as good as that in brain to predict delayed neurotoxicity [38].…”