Wang Xu, Zhang Huahai, Huang Lingli, Pan Yuanhu, Li Juan, Chen Dongmei, Cheng Guyue, Hao Haihong, Tao Yanfei, Liu Zhenli, Yuan Zonghui
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.
Chem Res Toxicol. 2015 Mar 16;28(3):470-81. doi: 10.1021/tx5004326. Epub 2015 Feb 13.
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.
喹喔啉 1,4 - 二氧化物（QdNOs）是具有广泛生物活性的合成剂。然而，QdNOs介导的DNA损伤机制尚不清楚。使用五种经典的QdNOs，喹烯酮（QCT）、乙酰甲喹（MEQ）、卡巴氧（CBX）、喹乙醇（OLA）和喹赛多（CYA），来研究QdNOs的遗传毒性。推测QdNOs的脱氧率在其遗传毒性中起作用。使用液相色谱/质谱 - 离子阱/飞行时间质谱（LC/MS - IT/TOF）研究了QdNOs在大鼠和猪肝微粒体中的脱氧率，并通过高效液相色谱（HPLC）实现了它们的相对定量。为了揭示脱氧率与遗传毒性之间的关系，检测了细胞损伤、氧化应激和DNA损伤。在低氧条件下，大鼠和猪肝微粒体中脱氧和双脱氧率的排序分别为QCT < CBX < MEQ < OLA < CYA和QCT < MEQ < CBX < OLA < CYA。在有氧条件下仅检测到脱氧喹喔啉。低氧条件下脱氧代谢物的浓度比有氧条件下至少高6倍。在大鼠、猪原代肝细胞和HepG2细胞中，氧化应激指标和DNA损伤与脱氧率呈负相关，表明QdNOs的脱氧率，尤其是双脱氧率，可能在介导其促进DNA损伤的能力中起关键作用。这些结果表明，QdNOs更快的脱氧导致较低的DNA损伤诱导毒性。我们的结果为预防QdNOs介导的DNA损伤提供了新的线索，并有助于理解QdNOs的化学结构、代谢和DNA损伤之间的关系。
