Maturational differences in chlorpyrifos-oxonase activity may contribute to age-related sensitivity to chlorpyrifos.
Chlorpyrifos (CPF), a commonly used cholinesterase-inhibiting insecticide, is lethal at much lower doses to young animals than adults. To explain this higher sensitivity in younger animals, we hypothesized that young rats have less chlorpyrifos-oxonase (CPFOase) activity than adults. To test this hypothesis, CPFOase activity was measured in the brain, plasma, and liver of male, postnatal day 4 (PND4) and adult (PND90) Long-Evans rats. CPFOase is biochemically defined as a Ca(2+)-dependent A-esterase that hydrolyzes chlorpyrifos-oxon (CPFO), the active metabolite of CPE. No brain CPFOase activity was detected at either age. Plasma and liver CPFOase activities were markedly lower at PND4 compared to adult: PND4 plasma and liver CPFOase activities were 1/11 and 1/2 the adult plasma and liver activities, respectively. Because the Km of CPFOase activity was high (i.e., 210-380 microM), it was important to determine if this CPFOase activity could hydrolyze physiologically relevant concentrations (i.e., nM to low microM) of CPFO. This was accomplished by comparing the shifts in the tissue acetylcholinesterase (AChE) IC50 for CPFO in the presence or absence of CPFOase activity. One would expect an increase in the "apparent" IC50 if CPFOase hydrolyzes substantial amounts of CPFO during the 30 minutes the tissue is preincubated with the CPFO. In the adult, both plasma and liver AChE apparent IC50 values were higher in the presence of CPFOase activity, suggesting that the CPFOase in those tissues was capable of hydrolyzing physiologically relevant concentrations of CPFO within 30 minutes. In young animals, however, there was less of a shift in the IC50 curves compared to the adult, confirming that the young animal has less capacity than the adult to detoxify physiologically relevant concentrations of CPFO via CPFOase.
Mortensen
S R
SR
Cellular and Molecular Toxicology Branch, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Chanda
S M
SM
Hooper
M J
MJ
Padilla
S
S
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D004390:Chlorpyrifos / Q000633:toxicity*; D004950:Esterases / Q000097:blood / Q000378:metabolism*; D005260:Female; D007306:Insecticides / Q000633:toxicity; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D008297:Male; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D007306:Insecticides; D004950:Esterases; D000110:Acetylcholinesterase; C107247:chlorpyrifos-oxonase; D004390:Chlorpyrifos