Evaluation of the safety of primary metabolites of cyadox: Acute and sub-chronic toxicology studies and genotoxicity assessment

Qin, Hui; Ihsan, Awais; Guo, Ping; Luo, Xun; Cheng, Guyue; Hao, Haihong; Chen, Dongmei; Jamil, Farrukh; Yue, Tao; Wang, Xu; Zhang, Yuan

doi:10.1016/j.yrtph.2015.11.011

Cited by 17 publications

(13 citation statements)

References 37 publications

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“…Moreover, it had been proved that Bisdeoxycarbadox, the bisdeoxy metabolite of carbadox, was positive in the Ames test and cell transformation test, its tumorigenic potential was apparently greater than that of the parent drug (FAO/WHO, ). However, there was no evidence for genotoxic activity of Cy1 in the bacterial reverse mutation test, mouse bone marrow micronucleus assay, or an in vitro assay for clastogenicity (Huang et al., ), indicating cyadox may not share the safety concerns of carbadox.…”

Section: Discussionmentioning

confidence: 99%

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp

Huang

Qiu

Sun

et al. 2017

Vet Pharm & Therapeutics

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The tissue kinetics of cyadox, an antibacterial agent used in food animals, and its major metabolites in pigs, chickens, and carp were investigated followed by a complete dietary exposure assessment to evaluate the food safety of cyadox. Cyadox and its major metabolites, bisdeoxycyadox (Cy1), 4-desoxycyadox (Cy2), N-(quinoxaline-2-methyl)-cyanide acetyl hydrazine (Cy4), quinoxaline-2-carboxylic acid (Cy6), and 2-hydrometh yl-3-hydroxy-quinoxaline (Cy12), were simultaneously quantitated with a highperformance liquid chromatography−ultraviolet (HPLC-UV) method. Pigs, chickens, and carp were fed with 150 mg/kg cyadox in feed for consecutive 60, 40, and 30 days, respectively. The residue amount of cyadox and its major metabolites in liver, kidney, muscle, and fat (skin) tissues was determined. Cy2 was below the limit of quantitation even at the withdrawal time of 6 hr, cyadox, Cy4, Cy6, and Cy12 could be detected at 6-24 hr with low level less than 50 μg/kg. By contrast, Cy1 persisted for 3 days in the kidney of pigs and chickens, and in the liver of carp. Based on these residue depletion data and previous toxicology results, the global estimated chronic dietary exposure assessment of cyadox for general population was conducted, indicating a zero withdrawal time (WDT) may be appropriate for cyadox in food animals when used in feed for prolonged administration. These results provide analytical techniques and safety standards suitable for residue monitoring of cyadox in food animals.

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Section: Discussionmentioning

confidence: 99%

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp

Huang

Qiu

Sun

et al. 2017

Vet Pharm & Therapeutics

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“…The toxicity of quinoxaline-N-1 oxide was lower than quinoxaline-N1,N4-dioxide, and bidesoxyquinoxaline was almost nontoxic (Ihsan et al, 2010;Wang et al, 2011c). An acute toxicity test, a sub-chronic toxicity test, and a battery of three genotoxicity tests suggested that bidesoxy CYA, N4-desoxycyadox and N1-desoxycyadox are not genotoxic (Huang et al, 2016). The N!O reduction metabolite of MEQ, 2-isoethanol 4-desoxymequindox, was detected in the liver and spleen with an increase of SOD, and in the testes following the appearance of 8-OhdG after rats were exposed to MEQ (25, 55, 110 and 275 mg/kg diet) for 180 days, suggesting that 2-isoethanol 4-desoxymequindox might be involved in the organ toxicity induced by MEQ (Ihsan et al, 2011;Wang et al, 2011c).…”

Section: The Toxicity Of Qdnos and Their Metabolitesmentioning

confidence: 99%

“…In the subchronic 90-day feeding test in rats, high doses of MEQ led to a reduction in body weight of rats after exposure of rats to MEQ (55, 110 and 275 mg/kg diet) and induced hepatic and adrenal histological changes as well as leaking of different serum constituents (Ihsan et al, 2010). CYA was thought to be a potential replacement for OLA in China (Huang et al, 2016). Compared with other QdNOs, CYA showed good safety in mutagenicity studies (Huang et al, 2016;Ihsan et al, 2013aIhsan et al, , 2013b, 90-day feeding studies , teratogenicity and reproduction studies , chronic studies (Wang et al, 2011b) and carcinogenicity studies (Sevcik, 1986).…”

Section: Introductionmentioning

confidence: 99%

“…CYA was thought to be a potential replacement for OLA in China (Huang et al, 2016). Compared with other QdNOs, CYA showed good safety in mutagenicity studies (Huang et al, 2016;Ihsan et al, 2013aIhsan et al, , 2013b, 90-day feeding studies , teratogenicity and reproduction studies , chronic studies (Wang et al, 2011b) and carcinogenicity studies (Sevcik, 1986). On the other hand, it has also been shown that QdNOs have potential phototoxic and photoallergic effects in farm workers.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Previous studies demonstrated that these drugs were active to many pathogenic microorganisms, including Escherichia coli, Salmonella spp., Staphylococcus aureus, Pasteurella multocida, Brachyspira hyodysenteriae, etc. [5].Cyadox (CYA) is a new member of QdNOs, which may substitute olaquindox and carbadox because of its low toxicity and broad antibacterial spectrum [6][7][8][9]. Over the last two decades, many papers have been published, in which both synthesis and biological activity assessment of a large number of QdNOs derivatives have been described [10,11].…”

Section: Introductionmentioning

confidence: 99%

In vitro antimicrobial activities of animal-used quinoxaline 1,4-di-N-oxides against mycobacteria, mycoplasma and fungi

et al. 2016

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BackgroundThe quinoxaline 1,4-di-N-oxides (QdNOs) were known as potent antibacterial agents. For the purpose of evaluating the bioactivity of existing animal-used QdNOs drugs against representative pathogenic microorganism, the representative drugs of quinoxalines including cyadox, mequindox, quinocetone and their metabolites were submitted to the in vitro evaluation for antituberculosis, antimycoplasma, antifungal and antiviral activities.ResultsIn antituberculosis assays, the prototype compounds were active (MIC = 4 ~ 8 μg/mL) against Mycobacterium tuberculosis H37Rv and M. bovis. Combined antimicrobial susceptibility test indicated that cyadox, mequindox and quinocetone combined with rifampicin had additive effect against M. tuberculosis complex with Fractional Inhibitory Concentration Index (FIC) of 0.75. Results of antifungal assays showed that quinocetone was active against Microsporum canis with MIC of 8 μg/mL. Antimycoplasma screening showed a generally good activity of quinocetone against Mycoplasma gallisepticum and Mycoplasma hyopneumoniae, with MIC between 8 and 16 μg/mL. As shown from the combined antimicrobial susceptibility test, cyadox, mequindox and quinocetone combined with tetracycline had additive effect against Mycoplasma gallisepticum with FIC of 0.75. These compounds were also submitted to antiviral assay against infectious bursal disease virus, porcine reproductive and respiratory syndrome virus, porcine parvovirus and classical swine fever virus. The results obtained showed that these QdNOs and their metabolites have no inhibitory activity against these viruses in vitro.ConclusionsQdNOs exhibit antimicrobial activities against mycobacteria, mycoplasma and fungi. This study gives new insight in further application of QdNOs and offers a way to promote the healthcare of animal husbandry.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0812-7) contains supplementary material, which is available to authorized users.

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Evaluation of the safety of primary metabolites of cyadox: Acute and sub-chronic toxicology studies and genotoxicity assessment

Cited by 17 publications

References 37 publications

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp

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

In vitro antimicrobial activities of animal-used quinoxaline 1,4-di-N-oxides against mycobacteria, mycoplasma and fungi

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