Metabolism of mequindox in liver microsomes of rats, chicken and pigs

Abstract

Mequindox, 3-methyl-2-quinoxalinacetyl-1,4-dioxide, is a quinoxaline-N,N-dioxide used in veterinary medicine as a antibacterial in China. To gain an understanding of the interspecies differences in the metabolism of mequindox, comparative metabolite profiles were qualitatively and quantitatively carried out for the first time in rat, chicken and pig liver microsomes by high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. A total of 14 metabolites were characterized based on their accurate MS(2) spectra and known structure of mequindox. The in vitro metabolic pathways of mequindox in three species were proposed as N-->O group reduction, carbonyl reduction, N-->O group reduction followed by carbonyl reduction or methyl mono-hydroxylation. A metabolic pathway involving N-->O group reduction followed by acetyl group mono-hydroxylation in only chicken was also proposed. There was also quantitative species difference for mequindox metabolism in three species. 1-Desoxymequindox was the main metabolite in all species, but otherwise there were some qualitative interspecies differences in mequindox major metabolites. This work has revealed biotransformation characteristics of mequindox among different species, and moreover will further facilitate the explanations of the biological activities of mequindox in animals.

The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

“…AO, acridine orange; cCBR1, chicken carbonyl reductase 1; porcine carbonyl reductase 1; SsAOX1, porcine aldehyde oxidase. Cited from (Chen et al, 2013;Huang et al, 2015bHuang et al, , 2015cLi et al, 2014aLi et al, , 2014bLiu et al, 2008Liu et al, , 2009Liu et al, , 2010aLiu et al, , 2010bLiu et al, , 2010cLiu et al, , 2011aLiu et al, , 2011bLiu & Sun, 2013;Mu et al, 2014;Tang et al, 2012;Wang et al, 2016b;Yang et al, 2013a;Zheng et al, 2011). marked as less genotoxicity than other kinds Wang et al, , 2011b.…”

“…A metabolic pathway involving N!O group reduction followed by acetyl group mono-hydroxylation was only revealed in chicken when MEQ was incubated in liver microsomes of rats, chicken, and pigs. Although 1-desoxymequindox was the main metabolite in rats, chicken, and pigs, there were some qualitative interspecies differences in MEQ major metabolites (Liu et al, 2010c). In the metabolism of OLA in liver microsomes and the cytosol of rats, pigs and chicken, thirteen metabolites were identified in rat liver microsomes, whereas only seven of these metabolites were detected in pig and chicken microsomes (Liu et al, 2010b).…”

“…To QCT, 27 phase-I metabolites were identified as 11 reduction metabolites, three direct hydroxylation metabolites, and 13 metabolites with a combination of reduction and hydroxylation (Liu et al, 2010a). The in vitro metabolic pathways of MEQ in three species were proposed as N!O group reduction, carbonyl reduction, N!O group reduction followed by carbonyl reduction or methyl mono-hydroxylation (Liu et al, 2010c). Liu et al documented that CYA was metabolized to seven metabolites in liver microsomes including three reduced metabolites (cyadox 1-monoxide, cyadox 4-monoxide and bisdesoxy cyadox), three hydrolysis metabolites of the amide bond (N-decyanoacetyl cyadox, N-decyanoacetyl cyadox 1-monoxide and N-decyanoacetyl bisdesoxy cyadox) and a hydroxylation metabolite of cyadox 1-monoxide (Liu et al, 2009).…”

“…The studies revealed that N!O group reduction is the main metabolic pathway of QdNOs metabolism (Huang et al, 2015a(Huang et al, , 2015bLi et al, 2014aLi et al, , 2014bLiu et al, 2008Liu et al, , 2009Liu et al, , 2010aLiu et al, , 2010bLiu et al, , 2010cLiu & Sun, 2013). The N!O group reduction of QdNOs might lead to the formation of reactive oxygen species (ROS) and oxidative stress Ihsan et al, 2010).…”

“…MEQ was also efficacious in the treatment of clinical infections caused by Treponeme, Pasteurella, Staphylococcus aureus, E. coli and Salmonella sp. and is widely used in the foodproducing animals by veterinarians in China (Ding et al, 2012;Ihsan et al, 2011Ihsan et al, , 2013aLiu et al, 2010c). CYA is a synthetic quinoxaline derivative, which has been developed and tested in China.…”