Rat brain acetylcholinesterase activity: developmental profile and maturational sensitivity to carbamate and organophosphorus inhibitors.
A growing body of evidence indicates that young animals exhibit an increased susceptibility to the lethal effects of cholinesterase (ChE)-inhibiting insecticides. Our laboratory is engaged in defining factors which may explain this age-related sensitivity. This report includes results from experiments designed to compare the developmental profiles, kinetic parameters and intrinsic (i.e. in vitro) sensitivity of developing male rat brain acetylcholinesterase (AChE) activity to carbamate and organophosphorus anticholinesterases. Total ChE activity in whole brain for each age was composed of about 90% AChE and 10% butyrylcholinesterase (BuChE) activity for the six ages examined. Brain AChE activity showed an age-related increase in Vmax until postnatal day 17 with no change in Km (average of all six ages approximately equal to 72 microM). Optimal substrate (acetylthiocholine) concentration for each age was 1 mM, and there was substrate inhibition (approximately 10%) at 2.5 mM. IC50s (the concentration of compound that inhibits 50% of the AChE activity in 30 min at 26 degrees C) defined concomitantly for postnatal day 4 and adult brain AChE using either aldicarb, carbaryl, chlorpyrifos-oxon or malaoxon were virtually identical at both ages with average IC50 values being: aldicarb = 2.4 microM, carbaryl = 1.7 microM, chlorpyrifos-oxon = 4.9 nM and malaoxon = 140 nM. In summary, AChE in young and adult brain differs mostly in specific activity while the Km(s), substrate profiles, and in vitro sensitivity to selected anticholinesterase insecticides are not different. Therefore, these data support the hypothesis that the greater sensitivity of the young animals to anticholinesterase pesticides is not due to the greater sensitivity of the target molecule AChE to these inhibitors.
Mortensen
S R
SR
Cellular and Molecular Toxicology Branch, Neurotoxicology Division (MD-74B), US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Hooper
M J
MJ
Padilla
S
S
D000110:Acetylcholinesterase / Q000378:metabolism*; D000367:Age Factors; D000448:Aldicarb / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005260:Female; D007306:Insecticides / Q000494:pharmacology*; D008294:Malathion / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051381:Rats
D002800:Cholinesterase Inhibitors; D007306:Insecticides; C100082:malaoxon; D000448:Aldicarb; D000110:Acetylcholinesterase; D008294:Malathion