Toxic metabolites, MAPK and Nrf2/Keap1 signaling pathways involved in oxidative toxicity in mice liver after chronic exposure to Mequindox

Abstract

Mequindox (MEQ) is a synthetic antimicrobial agent of quinoxaline-1,4-dioxide group (QdNOs). The liver is regarded as the toxicity target of QdNOs, and the role of N → O group-associated various toxicities mediated by QdNOs is well recognized. However, the mechanism underlying the in vivo effects of MEQ on the liver, and whether the metabolic pathway of MEQ is altered in response to the pathophysiological conditions still remain unclear. We now provide evidence that MEQ triggers oxidative damage in the liver. Moreover, using LC/MS-ITTOF analysis, two metabolites of MEQ were detected in the liver, which directly confirms the potential connection between N → O group reduction metabolism of MEQ and liver toxicity. The gender difference in MEQ-induced oxidative stress might be due to adrenal toxicity and the generation of M4 (2-isoethanol 1-desoxymequindox). Furthermore, up-regulation of the MAPK and Nrf2-Keap1 family and phase II detoxifying enzymes (HO-1, GCLC and NQO1) were also observed. The present study demonstrated for the first time the protein peroxidation and a proposal metabolic pathway after chronic exposure of MEQ, and illustrated that the MAPK, Nrf2-Keap1 and NF-кB signaling pathways, as well as the altered metabolism of MEQ, were involved in oxidative toxicity mediated by MEQ in vivo.

Mechanisms of the Testis Toxicity Induced by Chronic Exposure to Mequindox

“…In the present study, an accuracy error threshold of ±20 ppm was set as a limit to the calculation of possible elemental compositions. The identification of MEQ and its metabolites were also based on the recent reports ( Huang et al, 2015 ; Liu et al, 2017 ).…”

“…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 ). The genotoxicity induced by QCT, OLA and MEQ was found to be closely related to oxidative stress ( Zou et al, 2009 ; Huang et al, 2010 ; Liu W.Y.…”

“…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 ).…”

“…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 ). It was revealed that oxidative stress and metabolites of MEQ were regarded as important toxicity mechanisms in in vivo models of the adrenal gland ( Huang et al, 2009 ), liver ( Wang et al, 2011b ; Liu et al, 2017 ), spleen ( Wang et al, 2011b ), and endocrine and reproductive system ( Ihsan et al, 2011 ).…”

“…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 ). It was revealed that oxidative stress and metabolites of MEQ were regarded as important toxicity mechanisms in in vivo models of the adrenal gland ( Huang et al, 2009 ), liver ( Wang et al, 2011b ; Liu et al, 2017 ), spleen ( Wang et al, 2011b ), and endocrine and reproductive system ( Ihsan et al, 2011 ). The in vitro adrenal toxicity study on H295R cells that originated from a human adrenocortical carcinoma has further confirmed this conclusion ( Wang et al, 2016c ).…”