title: Deoxidation rates play a critical role in DNA damage mediated by important synthetic drugs, quinoxaline 1,4-dioxides.
abstract: Quinoxaline 1,4-dioxides (QdNOs) are synthetic agents with a wide range of biological activities. However, the mechanism of DNA damage mediated by QdNOs is far from clear. Five classical QdNOs, quinocetone (QCT), mequindox (MEQ), carbadox (CBX), olaquindox (OLA), and cyadox (CYA), were used to investigate the genotoxicity of QdNOs. The deoxidation rate of QdNOs was presumed to play a role in their genotoxicity. Deoxidation rates of QdNOs in both rat and pig liver microsomes were investigated using LC/MS-IT/TOF, and their relative quantification was achieved with HPLC. To reveal the relationships between the deoxidation rate and genotoxicity, cell damage, oxidative stress, and DNA damage were detected. Under low oxygen conditions, the rank order of the desoxy and bidesoxy rates in rat and pig liver microsomes was QCT < CBX < MEQ < OLA < CYA and QCT < MEQ < CBX < OLA < CYA, respectively. Only desoxy-quinoxalines were detected under aerobic conditions. The concentrations of deoxidized metabolites under low oxygen conditions were at least 6 times higher than those under aerobic conditions. In rats, porcine primary hepatocytes, and HepG2 cells, oxidative stress indices and DNA damage showed inverse relationships with the deoxidation rate, indicating that the deoxidation rate of QdNOs, especially bidesoxy rates, might play a critical role in mediating their ability to promote DNA damage. These results indicated that faster deoxidation of QdNOs results in lower DNA-damage-induced toxicity. Our results shed new light on the prevention of DNA damage mediated by QdNOs and help to understand the relationships among the chemical structures, metabolism, and DNA damage of QdNOs.
authors.affiliation: National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, ‡MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University , Wuhan, Hubei 430070, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Huahai
authors.initials: H
authors.lastname: Zhang
authors.forename: Lingli
authors.initials: L
authors.lastname: Huang
authors.forename: Yuanhu
authors.initials: Y
authors.lastname: Pan
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Dongmei
authors.initials: D
authors.lastname: Chen
authors.forename: Guyue
authors.initials: G
authors.lastname: Cheng
authors.forename: Haihong
authors.initials: H
authors.lastname: Hao
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Tao
authors.forename: Zhenli
authors.initials: Z
authors.lastname: Liu
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D011810:Quinoxalines / Q000633:toxicity*; D017208:Rats, Wistar; D013552:Swine
chemical_list: D011810:Quinoxalines; D010100:Oxygen