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

Abstract

Quinoxaline 1,4-dioxide derivatives (QdNOs) have been widely used as growth promoters and antibacterial agents. Carbadox (CBX), olaquindox (OLA), quinocetone (QCT), cyadox (CYA) and mequindox (MEQ) are the classical members of QdNOs. Some members of QdNOs are known to cause a variety of toxic effects. To date, however, almost no review has addressed the toxicity and metabolism of QdNOs in relation to oxidative stress. This review focused on the research progress associated with oxidative stress as a plausible mechanism for QdNO-induced toxicity and metabolism. The present review documented that the studies were performed over the past 10 years to interpret the generation of reactive oxygen species (ROS) and oxidative stress as the results of QdNO treatment and have correlated them with various types of QdNO toxicity, suggesting that oxidative stress plays critical roles in their toxicities. The major metabolic pathways of QdNOs are N→O group reduction and hydroxylation. Xanthine oxidoreductase (XOR), aldehyde oxidase (SsAOX1), carbonyl reductase (CBR1) and cytochrome P450 (CYP) enzymes were involved in the QdNOs metabolism. Further understanding the role of oxidative stress in QdNOs-induced toxicity will throw new light onto the use of antioxidants and scavengers of ROS as well as onto the blind spots of metabolism and the metabolizing enzymes of QdNOs. The present review might contribute to revealing the QdNOs toxicity, protecting against oxidative damage and helping to improve the rational use of concurrent drugs, while developing novel QdNO compounds with more efficient potentials and less toxic effects.

GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

“…Numerous studies have shown the toxicity of olaquindox in vivo [ 12 , 13 ], but it is more important to evaluate the genotoxicity and cytotoxicity of olaquindox. Previous studies have shown that olaquindox could induce marked cytoxicity and genotoxicity in African green monkey cell lines (Vero cells) and HepG2 cells [ 7 , 14 ].…”

Annulation of o‐Aminoquinoxaline‐1,4‐dioxidenitrile with Ketonic Compounds Under Friedländer‐type Cyclocondensation and its Biological Evaluation

“…The more convenient method for the synthesis of the starting material 2‐amino‐3‐cyano‐6‐methylquinoxaline‐1,4‐dioxide ( 3 ) by the reaction of 5‐methylbenzo[ c ] oxadiazole1‐oxide with malononitrile in the presence of triethylamine as a catalyst and DMF as a solvent was achieved. The scarlet red product was identified as component 3 with 75% yield and melting point 220–222°C .…”

“…Quinoxaline‐1,4‐dioxide derivatives are a class of substances possessing a broad spectrum of pharmacological activities, such as anticancer especially in solid tumor treatment , hypoxia‐selective activity , antibacterial , antifungal , and antimycobacterial . Quinoxaline‐1,4‐dioxide derivatives with three fused membered rings show a significant pharmaceutical importance , for example, pyridoquinoxaline, which is used as anticonvulsant and imidazoquinoxaline as receptor antagonists .…”

TCS2 Increases Olaquindox-Induced Apoptosis by Upregulation of ROS Production and Downregulation of Autophagy in HEK293 Cells

“…Olaquindox is used as a feed additive, but the toxic effects of olaquindox have drawn public attention. A large number of animal studies have revealed that oxidative stress damage in mice tissues, including liver, kidney and adrenal gland, could be caused by treatment with QdNOs such as olaquindox, quinocetone, carbadox and their metabolites [ 7 , 21 , 22 ]. Nevertheless, molecular mechanism research in an in vitro model is particularly important.…”

“…Oxidative stress damage, caused by excessive reactive oxygen species (ROS), has been suggested as a plausible mechanism for QdNO-induced toxicity and metabolism studies suggest that oxidative stress plays a critical role in QdNOs-induced cytotoxicity [ 7 ]. It has been inferred that the genotoxic effects caused by olaquindox were perhaps due to ROS-induced oxidative DNA damage in human hepatoma G2 (HepG2) cells [ 3 ].…”