Schulz-Jander Daniel A, Leimkuehler William M, Casida John E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Chem Res Toxicol. 2002 Sep;15(9):1158-65. doi: 10.1021/tx0200360.
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.
主要杀虫剂吡虫啉（IMI）已知可通过人细胞色素P450 3A4与NADPH经咪唑烷羟基化和脱氢作用分别代谢生成5-羟基吡虫啉和烯烃，还可通过硝基亚胺还原和裂解生成亚硝基亚胺、胍和尿素衍生物。人或兔肝微粒体在有NADPH存在时或兔肝细胞溶胶在未添加辅因子时对IMI进行的更广泛代谢会将IMI的N-硝基还原为N-氨基取代基，即相应的腙。在人微粒体-NADPH系统中孵育IMI时的一种主要代谢产物通过液相色谱/质谱法初步鉴定为源自腙的1,2,4-三唑-3-酮；腙与氯甲酸乙酯反应也可得到相同产物。在此将腙和推测的三唑酮一起（称为腙）进行定量分析。微粒体对硝基亚胺取代基的还原和裂解只有一部分归因于CYP450酶。向细胞溶胶酶转化为腙的过程中添加辅因子（NAD > NADH > NADP > NADPH）会产生抑制作用，而用氩气而非空气气氛则会增强这种转化。起作用的细胞溶胶酶似乎不是DT-黄递酶（几种新烟碱类会对其产生抑制作用）、醛糖还原酶、醛还原酶或黄嘌呤氧化酶。然而，几种醛糖酮还原酶抑制剂（即阿雷司他汀、EBPC、泊那司他、苯巴比妥和槲皮素）会抑制IMI的细胞溶胶代谢。其他带有硝基亚胺、亚硝基亚胺和硝基亚甲基取代基的新烟碱类可能也会被“新烟碱类硝基还原酶”代谢，因为它们可作为[(3)H]IMI代谢的竞争性底物。
