| 16153789 |
Honda H, Tomizawa M, Casida JE: Neo-nicotinoid metabolic activation and inactivation established with coupled nicotinic receptor-CYP3A4 and -aldehyde oxidase systems. Toxicol Lett. 2006 Feb 20;161(2):108-14. Epub 2005 Sep 8.
Two important enzymes in metabolism of the principal neo-nicotinoid insecticide imidacloprid are liver microsomal CYP3 A4 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 4beta 2. This study evaluates activation or inactivation of 11 neo-nicotinoids in a continuous two-step system coupling metabolism and receptor binding. For metabolism, the neo-nicotinoid 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 [(3) H] imidacloprid or the alpha4 beta2 nicotinic receptor and [(3) H](-)-nicotine are added to determine changes in neo-nicotinoid potency. With the Drosophila nAChR assay, the N-methyl compounds N-methyl-imidacloprid and thiamethoxam are activated 4.5-29-fold by CYP3 A4 whereas nine other neo-nicotinoids are not changed in potency. With the vertebrate alpha4 beta2 nAChR, AOX enhances imidacloprid potency but CYP3 A4 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. |
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