Mequindox Induced Genotoxicity and Carcinogenicity in Mice.

Qianying Liu,Zonghui Yuan,Deyu Huang,Qin Wu,Shuyu Xie,Zhixin Lei,Xu Wang,Yuanhu Pan

doi:10.3389/fphar.2018.00361

Abstract

Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.

Highlights

Quinoxaline-di-N-oxides (QdNOs), consisting of one or two acyclic chain moiety combined with quinoxaline ring, are a great family with the wide range of biological properties, including antibacterial, anti-candida, antitubercular, anticancer, antiprotozoal and growth promoting activities (Carta et al, 2005; Cheng et al, 2015; Vicente et al, 2009; Wang et al, 2011a, 2016b; Liu et al, 2017a)
CBX was administrated via i.p. and feed, the results suggested that CBX treated groups had a largest number of spontaneous and rare tumors, while a higher incidence of hepatic tumor was observed on rats that received CBX via i.p. (Sykora and Vortel, 1986)
An assessment of carcinogenicity potential of MEQ was carefully evaluated in KM mice using a dose level of 25, 55, and 110 mg/kg MEQ diet

Summary

Introduction

Quinoxaline-di-N-oxides (QdNOs), consisting of one or two acyclic chain moiety combined with quinoxaline ring, are a great family with the wide range of biological properties, including antibacterial, anti-candida, antitubercular, anticancer, antiprotozoal and growth promoting activities (Carta et al, 2005; Cheng et al, 2015; Vicente et al, 2009; Wang et al, 2011a, 2016b; Liu et al, 2017a). Mequindox ([3-methyl-2-acetyl] quinoxaline-1,4-dioxide, C11H10N2O3; MEQ) (Figure 1), a relative new compound in QdNOs, is a synthetic antibacterial agent with strong inhibitory effect against both Gram-positive and negative bacteria (Ihsan et al, 2010, 2011, 2013a). Mequindox was developed by the Lanzhou Institute of Animal Husbandry and Veterinary Drugs at the Chinese Academy of Agricultural Sciences. It was widely used in the food-producing animals in China due to its efficacious in the treatment of clinical infections caused by Treponeme, Pasteurella, E. coli, Staphylococcus aureus, and Salmonella sp. The previous studies revealed that long-term MEQ treatment induced adrenal (Huang et al, 2009), endocrine and reproductive system toxicity in Wistar rats (Ihsan et al, 2011). We found that MEQ produced toxicity in liver and testis of KM mice at a dose level of 25, 55, and 110 mg/kg diet (Liu et al, 2017b,c,d)

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Discussion

Conclusion