Further investigations into the genotoxicity of quinoxaline-di-N-oxides and their primary metabolites

Mechanisms of the Testis Toxicity Induced by Chronic Exposure to Mequindox

“…A lot of evidence suggested that the major metabolic pathway for QdNOs involves N →O group reduction ( Cheng et al, 2015 , 2016 ; Liu Q. et al, 2016 ), and that this type of metabolism is closely related to their toxicity ( Hao et al, 2006 ; Chen et al, 2008 , 2009 ). In this study, two metabolites of M4 and M8 were detected in the serum of male mice by LC/MS-IT-TOF analysis ( Figure 7 ), which directly confirms the potential connection of N →O group reduction metabolism of MEQ with its organ toxicity.…”

“…Therefore, apart from oxidative stress, the metabolite of M4 was another main factor in reproductive toxicity and the changes in testicular structure. M4 was a hydroxylated product of the side chain of N 1-MEQ, a partially reduced derivative of MEQ ( Liu and Sun, 2013 ; Huang et al, 2015 ; Liu Q. et al, 2016 ). Previous studies revealed that N 1-MEQ exhibited adrenal toxicity in H295R cells ( Wang et al, 2016c ) and genotoxicity in mice ( Liu Q. et al, 2016 ).…”

“…Mequindox (3-methyl-2-acetyl- N -1,4-dioxyquinoxaline, C 11 H 10 N 2 O 3 ; MEQ) ( Figure 1 ) is structurally similar to QdNOs, a group of chemicals consisting of one or two acyclic chain moieties combined with a quinoxaline ring. QdNOs are synthetic agents with a wide range of biological properties including antibacterial, anti-candida, anti-tubercular, anti-cancer, anti-protozoal and growth-promoting activities ( Wu et al, 2007 ; Vicente et al, 2009 ; Wang et al, 2011a , 2015 , 2016d ; Cheng et al, 2015 ; Liu Q. et al, 2016 ). Four QdNO derivatives, CBX, OLA, QCT and cyadox (CYA), have been developed for use in livestock and poultry farming, contributing to their significant antibacterial abilities and growth-promotion properties ( Wang et al, 2015 ; Zhang et al, 2015 ).…”

“…A large amount of evidence has suggested that the N →O group reduction is a major concerned metabolic pathway of QdNOs ( Cheng et al, 2015 , 2016 ; Liu Q. et al, 2016 ); accompanying this, some ROS and radical intermediates have emerged that ultimately cause oxidative stress ( Liu et al, 2017 ). It was revealed that oxidative stress plays a critical role in the damage caused by QdNOs such as apoptosis, DNA and lipid damage in vitro and in vivo ( Chowdhury et al, 2004 ; Azqueta et al, 2007 ; Yang et al, 2013 ; Zhang et al, 2014 ; Wang et al, 2015 ; Liu et al, 2017 ).…”

“…Importantly, apart from oxidative stress, the N →O group reduction metabolites of QdNOs were also found to be associated with their toxicity ( Hao et al, 2006 ; Chen et al, 2008 , 2009 ; Zhang et al, 2012 , 2015 ; Wang et al, 2015 ; Liu Q. et al, 2016 ; Liu et al, 2017 ). The primary metabolites of MEQ, N 1-MEQ and bidesoxy-mequindox, exhibited genotoxicity in in vitro and in vivo short-term tests ( Liu Q. et al, 2016 ). We recently showed that 2-isoethanol 1-desoxymequindox (M4) and 2-isoethanol 4-desoxymequindox (M8) ( Figure 1 ) were involved in liver toxicity in mice after exposure to MEQ for 11 months ( Liu et al, 2017 ).…”