Mequindox induced cellular DNA damage via generation of reactive oxygen species

Liu, Jing; Ouyang, Man; Jiang, Jun; Mu, Peiqiang; Wu, Jun; Yang, Qi; Zhang, Caihui; Xu, Weiying; Wang, Limin; Huen, Michael S.Y.; Deng, Yiqun

doi:10.1016/j.mrgentox.2011.10.012

Cited by 22 publications

(24 citation statements)

References 24 publications

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“…To determine the toxic effect of the carbonyl of MEQ, the toxicity of MEQ and the carbonyl-reduced MEQ, 2-isoethanol MEQ, to the HepG2 cells was tested by MTT assay. Consistent with previous reports on MEQ toxicity (Liu et al, 2012), the cell survival rates of HepG2 cells were inversely correlated to increasing concentrations of MEQ after 48-h treatment. The IC 50 of MEQ was 58.71 g/ml (Fig.…”

Section: Resultssupporting

confidence: 91%

Carbonyl Reduction of Mequindox by Chicken and Porcine Cytosol and Cloned Carbonyl Reductase 1

Tang¹,

Mu²,

Wu³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Mequindox (MEQ) is a novel synthetic quinoxaline 1,4-dioxides derivative, which is widely used as a veterinary drug and animal feed additive. However, the metabolic mechanism of MEQ is rarely reported. The N-oxide reduction mechanism of MEQ was reported in our previous work. In this article, the toxicity and the reduction of the carbonyl of MEQ were studied. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays demonstrated that the carbonyl-reduced MEQ, 2-isoethanol MEQ was much less toxic than MEQ. High-performance liquid chromatography analysis showed that the cytosol extracts of chicken and pig livers were able to reduce MEQ to 2-isoethanol MEQ and the reaction was NADPH-dependent. Further study via enzymeinhibitory experiment revealed that carbonyl reductase 1 (CBR1) participated in this metabolism. The enzyme activity analysis showed that both chicken CBR1 (cCBR1) and porcine CBR1 (pCBR1) were capable of catalyzing the carbonyl reduction of MEQ and its N-oxide reductive metabolite, 1-deoxymequindox. By comparison of the kinetic constants, we observed that the activity of cCBR1 was higher than pCBR1 to MEQ and the standard substrate of CBR1, menadione. On the other hand, both CBR1s exhibited higher activity to 1-deoxymequindox than MEQ. Mutation analysis suggested that the difference of amino acid at position 141/142 may be one possible reason that caused the activity difference between cCBR1 and pCBR1. Thus far, CBR1 was first reported to participate in the carbonyl reduction of MEQ. Our results will be helpful to recognize the metabolic pathways of quinoxaline drugs deeply and to provide a theoretical basis for controlling the negative effects of these drugs.

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Section: Resultssupporting

confidence: 91%

Carbonyl Reduction of Mequindox by Chicken and Porcine Cytosol and Cloned Carbonyl Reductase 1

Tang¹,

Mu²,

Wu³

et al. 2012

Drug Metab Dispos

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“…These different reagents include simple alkenes, 24 simple ketones, 25 β-diketones, 26,27 β-ketoesters, 28 β-ketoamides, 29 α-enamines 30 and malononitrile. 31 Herein, we utilized Beirut reaction to synthesize some new 6-chloroquinoxaline 1,4-dioxide derivatives from the reaction of 6-chlorobenzofuroxan (2) (Figure 1) with ethyl acetoacetate. These compounds covers some 2-arylidene-6-chloro-3-(ethoxycarbonyl)quinoxaline 1,4-dioxides, 8-chloro-1-oxo-2-substituted-1,2-dihydropyrido [3,4-b] quinoxaline 5,10-dioxide derivatives and some derivatives of 6-chloro-3-(hydrazinecarbonyl)-2-methylquinoxaline 1,4-dioxide.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Newly Fused 1,2-Dihydropyrido[3,4-b], Bridged Oxadiazol-2-yl, 4-Substituted-benzylidene Hydrazide and Arylidene 6-Chloroquinoxaline 1,4-Dioxides

Said

El-Ablack

Elbeheiry

2018

J. Braz. Chem. Soc.

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Some simple reactions using commercially available chemicals were used in the preparation of new biologically remarkable quinoxaline 1,4-dioxide derivatives. Several steps performed on 4-chloro-2-nitroaniline resulted in a quinoxaline 1,4-dioxide derivative, which reacted with dimethylformamide dimethylacetal (DMF-DMA) to produce an enamine. Transamination of this enamine with anilines gave the fused 1,2-dihydropyrido[3,4-b]quinoxaline 5,10-dioxide derivatives via an addition-elimination mechanism. Basic condensation reaction of quinoxaline active methyl afforded unexpected decarboxylated arylidene derivatives by using different aromatic aldehydes. Bridged oxadiazol-2-yl derivatives were obtained from the reaction of a hydrazide derivative with carbon disulfide and p-nitrobenzoic acid respectively. Whereas, acidic condensation of that hydrazide with aromatic aldehydes afforded the arylidene hydrazides.

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“…The notable effect of CBX and OLA on improving the rate of live weight gain and the efficiency of feed conversion was supposed to be primarily caused by stabilization of the intestinal microflora, improving the feed conversion and reducing the formation of toxins (Henderickx et al, 1982). Quinocetone (QCT, 3-methyl-2-quinoxalin benzenevinylketo-1,4-dioxide), mequindox (MEQ,, and cyadox (CYA, 2-formylquinoxaline-N1,N4-dioxide cyanocetylhydrazone), QdNO derivatives developed for use in animal production in China, were thought of highly due to their significant antibacterial properties and promotion-growth ability (Li et al, 2014a;Liu et al, 2012;Wu et al, 2012). It is generally believed that these drugs ameliorate intestinal microflora, improve protein utilization and increase protein synthesis in vivo (Carta et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…As already known, ROS generation and oxidative stress resulted from the reduction of QdNOs, which might result in wide damage such as apoptosis, and DNA, lipid and protein damage (Azqueta et al, 2007;Chowdhury et al, 2004;Wang et al, 2016a) in vivo or in vitro. During the past more than 10 years, there has been considerable focus on the potential of QdNOs to induce (Dai et al, 2015;Huang et al, 2010b;Li et al, 2015;Liu et al, 2012;Wang et al, 2015bWang et al, , 2016bWang et al, , 2015cYang et al, 2013bZhang et al, 2011Zhang et al, , 2013Zhang et al, , 2014Zhang et al, , 2015Zhao et al, 2013Zhao et al, , 2015Zou et al, 2009Zou et al, , 2011. Oxidative stress was also observed in rats Ihsan et al, 2010Ihsan et al, , 2011Wang et al, 2011c;Yu et al, 2014Yu et al, , 2013 and mice Zhao et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Martínez

Cheng

et al. 2016

Drug Metabolism Reviews

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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.

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Mequindox induced cellular DNA damage via generation of reactive oxygen species

Cited by 22 publications

References 24 publications

Carbonyl Reduction of Mequindox by Chicken and Porcine Cytosol and Cloned Carbonyl Reductase 1

Carbonyl Reduction of Mequindox by Chicken and Porcine Cytosol and Cloned Carbonyl Reductase 1

Synthesis and Characterization of Newly Fused 1,2-Dihydropyrido[3,4-b], Bridged Oxadiazol-2-yl, 4-Substituted-benzylidene Hydrazide and Arylidene 6-Chloroquinoxaline 1,4-Dioxides

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

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