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Nitroso-imidacloprid irreversibly inhibits rabbit aldehyde oxidase
Ryan A Dick1, David B Kanne, John E Casida
1Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112, USA.
Chemical Research in Toxicology
|November 16, 2007
Summary
Imidacloprid (IMI) metabolite, IMI-NO, is activated by aldehyde oxidase (AOX) into an irreversible inhibitor and a reactive intermediate. This process involves covalent binding to proteins, highlighting a novel metabolic activation pathway for neonicotinoid insecticides.
Area of Science:
- Biochemistry
- Enzymology
- Toxicology
Background:
- Imidacloprid (IMI) is a widely used neonicotinoid insecticide.
- Aldehyde oxidase (AOX) metabolizes IMI via aerobic nitroreduction.
- Rabbit liver AOX produces IMI-NO and IMI-NH2 from IMI.
Purpose of the Study:
- To investigate the metabolic fate of IMI-NO.
- To determine if IMI-NO acts as a time-dependent inactivator of AOX.
- To characterize the mechanism of AOX inactivation by IMI-NO.
Main Methods:
- Enzyme kinetics studies using partially purified AOX (ppAOX) and N-methylnicotinamide (NMN).
- Evaluation of IMI-NO's effect on AOX activity and inactivation rates.
- Ultrafiltration and [3H]IMI-NO labeling to assess binding and reversibility.
Main Results:
- IMI-NO inactivates AOX in an NMN-dependent manner at a significantly higher rate than NMN alone.
- IMI-NO inactivation is irreversible, with measured kinetic constants KI = 1.3 mM and kinact = 0.35 min(-1).
- Approximately 19% of reduced [3H]IMI-NO covalently binds to protein, a process attenuated by glutathione (GSH).
Conclusions:
- Rabbit liver AOX metabolically activates IMI-NO.
- This activation generates an irreversible AOX inhibitor and a reactive intermediate.
- The reactive intermediate covalently binds to proteins, indicating a potential toxicological mechanism.
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