Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants.
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 IC50 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.
Vose
Sarah C
SC
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, 115 Wellman Hall, University of California, Berkeley, CA 94720-3112, USA.
Holland
Nina T
NT
Eskenazi
Brenda
B
Casida
John E
JE
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000382:Agricultural Workers' Diseases / Q000097:blood / Q000201:enzymology; D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007306:Insecticides / Q000633:toxicity; D008214:Lymphocytes / Q000201:enzymology*; D051379:Mice; D009498:Neurotoxins / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011247:Pregnancy; D013379:Substrate Specificity
D007306:Insecticides; D009498:Neurotoxins; D009943:Organophosphorus Compounds; D000110:Acetylcholinesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human