Neonicotinoid insecticides: reduction and cleavage of imidacloprid nitroimine substituent by liver microsomal and cytosolic enzymes.
The major insecticide imidacloprid (IMI) is known to be metabolized by human cytochrome P450 3A4 with NADPH by imidazolidine hydroxylation and dehydrogenation to give 5-hydroxy-imidacloprid and the olefin, respectively, and by nitroimine reduction and cleavage to yield the nitrosoimine, guanidine, and urea derivatives. More extensive metabolism by human or rabbit liver microsomes with NADPH or rabbit liver cytosol without added cofactor reduces the IMI N-nitro group to an N-amino substituent, i.e., the corresponding hydrazone. A major metabolite on incubation of IMI in the human microsome-NADPH system is tentatively assigned by LC/MS as a 1,2,4-triazol-3-one derived from the hydrazone; the same product is obtained on reaction of the hydrazone with ethyl chloroformate. The hydrazone and proposed triazolone are considered here together (referred to as the hydrazone) for quantitation. Only a portion of the microsomal reduction and cleavage of the nitroimine substituent is attributable to a CYP450 enzyme. The cytosolic enzyme conversion to the hydrazone is inhibited by added cofactors (NAD > NADH > NADP > NADPH) and enhanced by an argon instead of an air atmosphere. The responsible cytosolic enzyme(s) does not appear to be DT-diaphorase (which is inhibited by several neonicotinoids), aldose reductase, aldehyde reductase, or xanthine oxidase. However, the cytosolic metabolism of IMI is inhibited by several aldo-keto-reductase inhibitors (i.e., alrestatin, EBPC, Ponalrestat, phenobarbital, and quercetin). Other neonicotinoids with nitroimine, nitrosoimine, and nitromethylene substituents are probably also metabolized by "neonicotinoid nitro reductase(s)" since they serve as competitive substrates for [(3)H]IMI metabolism.
Schulz-Jander
Daniel A
DA
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Leimkuehler
William M
WM
Casida
John E
JE
D000818:Animals; D002855:Chromatography, Thin Layer; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006146:Guanidines / Q000032:analysis / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000032:analysis / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D007097:Imines / Q000737:chemistry / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D000073943:Neonicotinoids; D009574:Nitro Compounds; D010084:Oxidation-Reduction; D010944:Plants; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D006835:Hydrazones; D007093:Imidazoles; D007097:Imines; D007306:Insecticides; D000073943:Neonicotinoids; D009574:Nitro Compounds; D011994:Recombinant Proteins; C082359:imidacloprid; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone)