Deoxidation Rates Play a Critical Role in DNA Damage Mediated by Important Synthetic Drugs, Quinoxaline 1,4-Dioxides

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), mequindor (MEQ), orbadox (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. Deoiddation 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 IOW oxygen conditions, the rank order of the desoxy and bidesoxy rates in tat and pig liver microsomes Was QCT < CBX < MEQ < OA < 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 4)1: 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.