Enzymes and Inhibitors in Neonicotinoid Insecticide Metabolism

Abstract

Neonicotinoid insecticide metabolism involves considerable substrate specificity and regioselectivity of the relevant CYP450, aldehyde oxidase, and phase II enzymes. Human CYP450 recombinant enzymes carry out the following conversions: CYP3A4, 2C19 and 2B6 for thiamethoxam (TMX) to clothianidin (CLO); 3A4, 2C19 and 2A6 for CLO to desmethyl-CLO; 2C19 for TMX to desmethyl-TMX. Human liver aldehyde oxidase reduces the nitro substituent of CLO to nitroso much more rapidly than that of TMX. Imidacloprid (IMI), CLO and several of their metabolites do not give detectable N-glucuronides but 5-hydroxy-IMI, 4,5-diol-IMI and 4-hydroxy-thiacloprid are converted to O-glucuronides in vitro with mouse liver microsomes and UDP-glucuronic acid or in vivo in mice. Mouse liver cytosol with S-adenosylmethionine converts desmethyl-CLO to CLO but not desmethyl-TMX to TMX. Two organophosphorus CYP450 inhibitors partially block IMI, thiacloprid and CLO metabolism in vivo in mice, elevating the brain and liver levels of the parent compounds while reducing amounts of the hydroxylated metabolites.

The influence of sublethal doses of imidacloprid on protein content and proteolytic activity in honey bees (Apis mellifera L.)

“…In our study, we used extracts from whole bees, so it is important to remember that proteases and inhibitors occur in many tissues and fulfill different functions in the biology of insects, from food secretion and digestion (Chapman, 1998;Deseyn & Billen, 2005;Li et al, 2008;Liu et al, 2013) to metamorphosis (Lima, BrochettoBraga, & Chaud-Netto, 2000;Malone, Todd, Burgess, & Christeller, 2004;Strachecka, Gryzińska, & Krauze, 2010;Strachecka, Paleolog, & Grzywnowicz, 2008) and immune mechanisms (Evans et al, 2006;Frączek et al, 2013). It is also well known that some enzymes fulfill detoxification functions, because they take part in the metabolism of pesticides (Shi et al, 2009). Another group is represented by a proteolytic system that catalyzes the hydrolytic degradation of peptide bonds and takes part in many biological processes (Costa & Cruz-Landim, 2005;Frączek et al, 2013;Lima et al, 2000;Strachecka et al, 2008Strachecka et al, , 2010Walter & Clélia, 1994).…”

“…In recent in vivo studies, it has also been shown that the sublethal doses of imidacloprid not only cause decrease in the size of HPGs but also in the respiratory rhythm of A. mellifera (Hatjina et al, 2013). Besides imidacloprid itself, its degradation products released as a result of its metabolism have a further effect on bees (Suchail et al, 2004;Simon-Delso et al, 2014) and the proteins showing enzymatic qualities constitute an interesting group of compounds involved in different biochemical processes in insects (Frączek, Ż ó łtowska, Lipiński, & Dmitryjuk, 2013;Shi, Dick, Ford, & Casida, 2009). Furthermore, all above-mentioned sublethal effects can also lead to losses of pollination services provided by honey bees and solitary bees .…”

Neonicotinoid Metabolism: Compounds, Substituents, Pathways, Enzymes, Organisms, and Relevance

“…33 CYP3A4 is also very effective for TMX conversion to CLO. 34 IMI resistance in Drosophila melanogaster correlates with Cyp6g1 overexpression and cross-resistance to DDT. 35 A binding site model has been presented for C5 hydroxylation of IMI by Bemisia tabaci CYP6CM1vQ (Figure 14).…”

“…63,64 A second type is the masked CLO derivatives including TMX, which is oxidatively metabolized by CYP450s to N-desmethyl-TMX and CLO, both potent insecticides or agonists. 24,34 Other compounds presumed to be pro-CLO derivatives are the TMX analogues with the -CH 2 OCH 2 -moiety replaced by -CH 2 SCH 2 -, -CH 2 -NHCH 2 -, and -CH 2 C(OCH 3 ) 2 CH 2 -undergoing chemical or metabolic conversion to CLO. 65,66 A third class of potential proneonicotinoids is the masked nitromethylene compounds with Mannich bases as the primary example.…”

Acute Poisoning with Neonicotinoid Insecticide

“…Clothianidin is demethylated by CYP 3A4, 2C19 and 2A6 [18]. There is no accumulation of neonicotinoids in the body: over 90% are eliminated in less than 24 h and totally in 48 h [15,19].…”