Journal
TOXICOLOGY LETTERS
Volume 161, Issue 2, Pages 108-114Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2005.08.004
Keywords
aldehyde oxidase; CYP3A4; metabolism; neonicotinoid; nicotinic receptor
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Funding
- NIEHS NIH HHS [R01 ES08424] Funding Source: Medline
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Two important enzymes in metabolism of the principal neonicotinoid insecticide imidacloprid are liver microsomal CYP3A4 and cytosolic aldehyde oxidase (AOX). CYP3A4 oxidation at several molecular sites and AOX reduction at the nitro substituent result in either an increase (activation) or decrease (inactivation) of agonist potency at nicotinic acetylcholine receptors (nAChRs), both insect and vertebrate alpha 4 beta 2. This study evaluates activation or inactivation of 11 nermicotinoids in a continuous two-step system coupling metabolism and receptor binding. For metabolism, the neonicotinoid is incubated with CYP3A4 and NADPH or AOX with the cosubstrate N-methyl-nicotinamide, terminating the reaction with ketoconazole or menadione, respectively, to inhibit further conversion. For receptor assay, either the Drosophila nAChR and [H-3]imidacloprid or the alpha 4 beta 2 nicotinic receptor and [H-3](-)-nicotine are added to determine changes in neonicotinoid potency. With the Drosophila nAChR assay, the N-methyl compounds N-methyl-imidacloprid and thiamethoxant are activated 4.5-29-fold by CYP3A4 whereas nine other neonicotinoids are not changed in potency. With the vertebrate alpha 4 beta 2 nAChR, AOX enhances imidacloprid potency but CYP3A4 does not. The AOX system coupled with the Drosophila receptor strongly inactivates clothianidin, dinotefuran, imidacloprid, desmethyl-thiamethoxam, and thiamethoxam with some inactivation of nitenpyram, and nithiazine, and little or no effect on four other compounds. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
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