Mechanistic Toxicodynamic Model for Receptor-Mediated Toxicity of Diazoxon, the Active Metabolite of Diazinon, in Daphnia magna

Kretschmann, Andreas, Ashauer, Roman, Hitzfeld, Kristina, Spaak, Piet, Hollender, Juliane and Escher, Beate I. (2011) Mechanistic Toxicodynamic Model for Receptor-Mediated Toxicity of Diazoxon, the Active Metabolite of Diazinon, in Daphnia magna. Environmental Science and Technology, 45 11: 4980-4987. doi:10.1021/es1042386


Author Kretschmann, Andreas
Ashauer, Roman
Hitzfeld, Kristina
Spaak, Piet
Hollender, Juliane
Escher, Beate I.
Title Mechanistic Toxicodynamic Model for Receptor-Mediated Toxicity of Diazoxon, the Active Metabolite of Diazinon, in Daphnia magna
Journal name Environmental Science and Technology   Check publisher's open access policy
ISSN 0013-936X
Publication date 2011-06-01
Year available 2011
Sub-type Article (original research)
DOI 10.1021/es1042386
Open Access Status
Volume 45
Issue 11
Start page 4980
End page 4987
Total pages 8
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
The organothiophosphate diazinon inhibits the target site acetylcholinesterase only after activation to its metabolite diazoxon. Commonly, the toxicity of xenobiotics toward
aquatic organisms is expressed as a function of the external concentration and the resulting effect on the individual level after fixed exposure times. This approach does not account for the time dependency of internal processes such as uptake, metabolism, and interaction of the toxicant with the target site. Here, we develop a
mechanistic toxicodynamic model for Daphnia magna and diazoxon, which accounts for the inhibition of the internal target site acetylcholinesterase and its link to the observable effect, immobilization, and mortality. The model was parametrized by experiments performed in vitro with the active metabolite diazoxon on enzyme extracts and in vivo with the parent compound diazinon. The mechanism of acetylcholinesterase inhibition was shown to occur irreversibly in two steps via formation of a reversible enzyme - inhibitor complex. The corresponding kinetic parameters revealed a very high sensitivity of acetylcholinesterase from D. magna toward diazoxon, which corresponds well with the high toxicity of diazinon toward this species. Recovery of enzyme activity but no recovery from immobilization was observed after in vivo exposure to diazinon. The toxicodynamicmodel combining all in vitro and in vivo parameters was successfully applied to describe the time course of immobilization in dependence of acetylcholinesterase activity during exposure to diazinon. The threshold value for enzyme activity below which immobilization set in amounted to 40% of the control activity.  Furthermore, the model enabled the prediction of the time-dependent diazoxon concentration directly present at the target site.
Keyword Acetylcholinesterase Activity
Brain Acetylcholinesterase
Organophosphorus Compounds
Cholinesterase Activity
Kinetic-Analysis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Received: December 17, 2010. Accepted: April 14, 2011. Revised: April 10, 2011. Published: May 03, 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
National Research Centre for Environmental Toxicology Publications
 
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