The mechanism of enzymatic and non-enzymatic N-oxide reductive metabolism of cyadox in pig liver.

Cyadox is a novel quinoxaline-1,4-dioxide with the potential for development as a substitute for the banned veterinary drugs carbadox and olaquindox. In this paper, using pigs as the test subjects, the metabolic mechanism of cyadox N-oxide reduction in liver is demonstrated. There exist two metabolic mechanisms for the N-oxide reduction of cyadox, the enzymatic and non-enzymatic routes. It is found that cyadox can be enzymatically reduced to 4-cyadox monoxide and 1-cyadox monoxide; this process is catalyzed by aldehyde oxidase and xanthine oxidase in the cytosol and by cytochrome b5 reductase in the microsomes. On the other hand, cyadox is only reduced to 4-cyadox monoxide in the non-enzymatic reduction mediated by heme groups of catalase and cytochrome P450s. We supposed that, owing to the position of the side chain in cyadox, the 1-N-oxide and 4-N-oxide bonds in the quinoxaline ring had different biochemical activities, which caused cyadox to be shunted to the distinct metabolic mechanisms. Additionally, this research gives the first evidence of FAD- and NAD(P)H-dependent non-enzymatic catalase reduction of a heterocyclic N-oxide. The research provides a basic foundation for the formulation of safety controls for animal products and the properties and metabolism of heterocyclic N-oxides.