title: Further investigations into the genotoxicity of quinoxaline-di-N-oxides and their primary metabolites.
abstract: 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.
authors.affiliation: 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.
authors.forename: Qianying
authors.initials: Q
authors.lastname: Liu
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
authors.forename: Jianwu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan.
authors.forename: Awais
authors.initials: A
authors.lastname: Ihsan
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
authors.forename: Xianglian
authors.initials: X
authors.lastname: Liu
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Menghong
authors.initials: M
authors.lastname: Dai
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Guyue
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Hao
authors.affiliation: Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China. Electronic address: wangxu@mail.hzau.edu.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China. Electronic address: yuan5802@mail.hzau.edu.cn.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D011810:Quinoxalines / Q000737:chemistry / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects*
chemical_list: D003497:Cyclic N-Oxides; D011810:Quinoxalines
keywords: Genotoxicity; Mequindox; Metabolites; Olaquindox; Quinocetone; Quinoxaline-di-N-Oxides