Long-term dose-dependent response of Mequindox on aldosterone, corticosterone and five steroidogenic enzyme mRNAs in the adrenal of male rats

Huang, Xian-Ju; Ihsan, Awais; Wang, Xu; Dai, Menghong; Wang, Yulian; Su, Shijia; Xue, Xi-Juan; Zhang, Yuan

doi:10.1016/j.toxlet.2009.08.021

Cited by 61 publications

(52 citation statements)

References 32 publications

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“…It exerts marked adrenal toxicities and mutagenicity. 1 However, to our knowledge, the absorption, distribution, metabolism, and excretion of mequindox in animals have not been reported till now. In general, knowledge of the metabolic fate of a compound is important because it affects clearance, half-life, and oral bioavailability and governs the outcome of pharmacodynamic and toxicological observation.…”

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confidence: 93%

Metabolism of mequindox in liver microsomes of rats, chicken and pigs

Liu

Huang

Chen

et al. 2010

Rapid Comm Mass Spectrometry

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Mequindox, 3-methyl-2-quinoxalinacetyl-1,4-dioxide, is a quinoxaline-N,N-dioxide used in veterinary medicine as a antibacterial in China. To gain an understanding of the interspecies differences in the metabolism of mequindox, comparative metabolite profiles were qualitatively and quantitatively carried out for the first time in rat, chicken and pig liver microsomes by high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. A total of 14 metabolites were characterized based on their accurate MS(2) spectra and known structure of mequindox. The in vitro metabolic pathways of mequindox in three species were proposed as N-->O group reduction, carbonyl reduction, N-->O group reduction followed by carbonyl reduction or methyl mono-hydroxylation. A metabolic pathway involving N-->O group reduction followed by acetyl group mono-hydroxylation in only chicken was also proposed. There was also quantitative species difference for mequindox metabolism in three species. 1-Desoxymequindox was the main metabolite in all species, but otherwise there were some qualitative interspecies differences in mequindox major metabolites. This work has revealed biotransformation characteristics of mequindox among different species, and moreover will further facilitate the explanations of the biological activities of mequindox in animals.

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confidence: 93%

Metabolism of mequindox in liver microsomes of rats, chicken and pigs

Liu

Huang

Chen

et al. 2010

Rapid Comm Mass Spectrometry

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“…However, it has been forbidden in poultry since 2000 due to its toxic side effects, which may explain the relatively low prevalence of oqxAB in the chicken farm. A new synthetic quinoxaline 1,4-dioxide (QdNO) derivative, mequindox (3-methyl-2-acetyl-N-1,4-dioxyquinoxaline; C 11 H 10 N 2 O 3 ), which was developed in China, has also been widely used as an antibacterial and animal feed additive in China since the 1990s (14). Antimicrobial usage in food animals is considered the most important factor in the selection of resistant bacteria (34).…”

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confidence: 99%

Prevalence and Dissemination of oqxAB in Escherichia coli Isolates from Animals, Farmworkers, and the Environment

Zhao

Zhang-liu

Chen

et al. 2010

Antimicrob Agents Chemother

137

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OqxAB has recently been identified as one of the mechanisms of plasmid-mediated quinolone resistance (PMQR).Compared to what is observed for other PMQR determinants, there is a paucity of data with regard to the prevalence and epidemiology of OqxAB and its contribution to resistance to different antimicrobials. In this study, the prevalence and dissemination of oqxAB and other PMQR genes in Escherichia coli isolates from animals, farmworkers, and the environment in 2002 in China were investigated. Of the 172 E. coli isolates, 39.0% carried oqxA, while only 4.1%, 2.9%, and 0.6% carried qnr (1 qnrB6 isolate, 5 qnrS1 isolates, and 1 qnrD isolate), qepA, and aac(6)-Ib-cr, respectively. Among the 33 isolates from farmworkers, 10 (30.3%) were positive for oqxA. oqxAB was associated with IS26 and was carried on the 43-to 115-kb IncF transferable plasmid. Transconjugants carrying oqxAB showed 4-to 16-fold increases in the MICs of quinolones, 16-to 64-fold increases in the MICs of quinoxalines, 8-to 32-fold increases in the MICs of chloramphenicol and trimethoprim-sulfamethoxazole, and 4-to 8-fold increases in the MICsof florfenicol compared to the levels for the recipient. The pulsed-field gel electrophoresis (PFGE) analysis showed that the high levels of prevalence and dissemination of oqxAB in E. coli in animal farms were primarily due to the transmission of plasmids carrying oqxAB, although clonal transmission between human and swine E. coli isolates was observed. It is concluded that oqxAB was widespread in animal farms in China, which may be due to the overuse of quinoxalines in animals. This study warrants the prudent use of quinoxalines in food animals.

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“…High dose of MEQ was observed to lead to cytotoxicity and organ toxicity in liver and spleen , kidney , testis , and adrenal gland (Huang et al, 2009) in animals. The N-oxide reductive metabolism of MEQ can lead to the increasing of the intracellular reactive oxygen species, which cause damage to lipids, sugars, amino acid chains, and DNA (Liu et al, 2003;Ellis, 2007).…”

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confidence: 99%

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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Long-term dose-dependent response of Mequindox on aldosterone, corticosterone and five steroidogenic enzyme mRNAs in the adrenal of male rats

Cited by 61 publications

References 32 publications

Metabolism of mequindox in liver microsomes of rats, chicken and pigs

Metabolism of mequindox in liver microsomes of rats, chicken and pigs

Prevalence and Dissemination of oqxAB in Escherichia coli Isolates from Animals, Farmworkers, and the Environment

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

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