Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Toxicol Sci. 2013 May;133(1):22-8. doi: 10.1093/toxsci/kft066. Epub 2013 Mar 5.
Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general.
醛氧化酶（AOX）在体外代谢许多外来物质，但相对于细胞色素 P450（CYPs）和其他解毒系统，其在体内的重要性通常未知。目前，最重要的杀虫剂是新烟碱类，它们在体外通过 AOX 还原硝基亚氨基基团和 CYP 通过氧化反应代谢。本研究的目的是使用小鼠模型确定 AOX 和 CYP 在体内的相对重要性。方法是通过在饮用水中提供钨或肼来降低肝 AOX 活性，或使用 AOX 缺陷的 DBA/2 小鼠品系。这些方法都没有降低使用同工酶非特异性底物在体外测量的 CYP 活性。与对照组相比，钨处理使肝 AOX 活性降低了 45%，肼处理降低了 61%，AOX 缺陷小鼠降低了 81%。当用主要的新烟碱类杀虫剂吡虫啉（IMI）腹腔注射处理小鼠时，CYP 氧化反应代谢没有明显受到影响，而 AOX 生成的亚硝胍代谢物则分别用钨、肼处理降低了 30%和 56%，在 AOX 缺陷小鼠中降低了 86%。另一种 IMI 硝基还原代谢物去硝吡虫啉，分别用钨、肼和 AOX 缺陷小鼠处理降低了 55%、65%和 81%。因此，三种不同的方法降低肝 AOX 活性，相应地降低了 IMI 处理的小鼠肝内的还原代谢物。用表达 AOX 和 AOX 缺陷的果蝇评估了 AOX 参与 IMI 代谢的可能性，但在两种菌株之间没有发现 IMI 硝基还原或敏感性的差异。这是首次在哺乳动物中建立 AOX 在新烟碱类代谢中的体内相关性的研究之一，也是首次对一般外来物质进行的研究之一。
