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.
Highlights
Quinoxaline-di-N-oxides (QdNOs) possessing the quinoxaline-1,4-dioxide basic structure, are known to be potent antibacterial agents with a wide range of biological properties[1,2,3,4,5,6,7]
We recently showed that MEQ could result in adrenal toxicity by oxidative stress in H295R cells that originated from a human adrenocortical carcinoma[28]
Previous studies have demonstrated that oxidative stress is associated with the in vitro toxicity of QdNOs, including cytotoxicity[26,46,52], adrenal toxicity[24,26], genotoxicity[5,6,25,27,46,53] and apoptosis[8,44,45,52,54,55,56,57]
Summary
Quinoxaline-di-N-oxides (QdNOs) possessing the quinoxaline-1,4-dioxide basic structure, are known to be potent antibacterial agents with a wide range of biological properties[1,2,3,4,5,6,7]. To date, it is not clear whether the activation of the MAPK, Nrf2-Keap[1] and NF-κB pathways participate in oxidative liver damage caused by MEQ though they have the same quinoxaline ring. Based on the above information, this study was designed to investigate the hypothesis that MEQ–induced liver toxicity was associated with oxidative stress, the metabolism of MEQ and the activation of the MAPKs, NF-κB, and Nrf2-Keap[1] signaling pathways.
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