Liu Qianying, Zhang Jianwu, Luo Xun, Ihsan Awais, Liu Xianglian, Dai Menghong, Cheng Guyue, Hao Haihong, Wang Xu, Yuan Zonghui
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
Food Chem Toxicol. 2016 Jul;93:145-57. doi: 10.1016/j.fct.2016.04.029. Epub 2016 May 8.
Quinoxaline-di-N-oxides (QdNOs) are potential antibacterial agents with a wide range of biological properties. Quinocetone (QCT), carbadox (CBX), olaquindox (OLA), mequindox (MEQ) and cyadox (CYA) are classical QdNOs. Though the genotoxicity of parent drugs has been evaluated, the genotoxicity of their primary N → O reduced metabolites remains unclear. In the present study, a battery of four different short-term tests, mouse lymphoma assay (MLA), Ames test, chromosomal aberration assay in vitro and bone marrow erythrocyte micronucleus assay in vivo was carried out to investigate the genotoxicity of the six primary N → O reduced metabolites. Additionally, the genotoxicity of five parent drugs was evaluated by the MLA. Strong genotoxicity of N1-MEQ, B-MEQ and B-CBX was found in three of the assays but not in the Ames assay, and the rank order was N1-MEQ>B-MEQ>B-CBX that is consistent with prototype QdNOs. Negative results for the five QdNOs were noted in the MLA. We present for the first time a comparison of the genotoxicity of primary N → O reduced metabolites, and evaluate the ability of five QdNOs to cause mutations in the MLA. The present study demonstrates that metabolites are involved in genetic toxicity mediated by QdNOs, and improve the prudent use of QdNOs for public health.
喹喔啉二氮氧化物（QdNOs）是具有广泛生物学特性的潜在抗菌剂。喹烯酮（QCT）、卡巴氧（CBX）、喹乙醇（OLA）、甲基喹乙醇（MEQ）和喹赛多（CYA）是典型的QdNOs。尽管已对母体药物的遗传毒性进行了评估，但其主要的N→O还原代谢产物的遗传毒性仍不清楚。在本研究中，进行了一系列四种不同的短期试验，即小鼠淋巴瘤试验（MLA）、艾姆斯试验、体外染色体畸变试验和体内骨髓红细胞微核试验，以研究六种主要的N→O还原代谢产物的遗传毒性。此外，通过MLA评估了五种母体药物的遗传毒性。在三项试验中发现N1-MEQ、B-MEQ和B-CBX具有较强的遗传毒性，但在艾姆斯试验中未发现，其排序为N1-MEQ>B-MEQ>B-CBX，这与原型QdNOs一致。在MLA中，五种QdNOs均呈阴性结果。我们首次比较了主要的N→O还原代谢产物的遗传毒性，并评估了五种QdNOs在MLA中引起突变的能力。本研究表明，代谢产物参与了QdNOs介导的遗传毒性，并促进了QdNOs在公共卫生方面的谨慎使用。
