糠菌唑在大鼠、小鼠、兔、狗和人肝微粒体中的立体选择性代谢  

Stereoselective metabolism of bromuconazole in liver microsomes from rat, mouse, rabbit, dog and human

作　　者：吴淑春[1,2] 韩剑众[1] 虞淼 章虎[4] 钱鸣蓉[4] WU Shuchun;HAN Jianzhong;YU Miao;ZHANG Hu;QIAN Mingrong(College of Food Science and Biotechnology,Zhejiang Gongshang University,Hangzhou 310018,China;Hangzhou Medical College,Hangzhou 310053,China;Agricultural Products Quality Supervision and Testing Center in Zhejiang Province,Hangzhou 310020,China;Institute of Quality and Standard on Agricultural Produhbcts,Zhejiang Academy of Agricultural Sciences,Hangzhou 310021,China)

机构地区：[1]浙江工商大学食品与生物工程学院,杭州310018 [2]杭州医学院,杭州310053 [3]浙江省农产品质量监督检验测试中心,杭州310020 [4]浙江省农业科学院农产品质量标准研究所,杭州310021

出　　处：《农药学学报》2020年第6期1008-1018,共11页Chinese Journal of Pesticide Science

基　　金：国家自然科学基金(21507114);杭州医学院自然科学基金(2016XZA01)。

摘　　要：采用高效液相色谱-串联质谱(HPLC-MS/MS)手性色谱柱法定量分析肝微粒体中的糠菌唑,通过密度泛函理论计算光谱与振动圆二色光谱(VCD)和红外光谱(IR)比对,确定了糠菌唑4种对映体的绝对构型;以大鼠、小鼠、兔、狗和人肝微粒体为模型,研究了糠菌唑的立体选择性降解行为。结果表明:在供试肝微粒体中,4种异构体的降解均遵循一级反应动力学方程,且在人和小鼠肝微粒体中的代谢速率相对较慢。(2S, 4R)-和(2R, 4S)-糠菌唑在5种供试肝微粒体中的立体选择性趋势一致,而(2R, 4R)-和(2S, 4S)-糠菌唑只在兔肝微粒体中的降解有显著的立体选择性差异,在小鼠肝微粒体中几乎没有立体选择性。酶促反应动力学结果也证实了糠菌唑代谢的立体选择性,并显示(2R, 4R)-和(2S, 4S)-糠菌唑在供试肝微粒体中的酶促反应趋势存在种属差异。Bromuconazole is a potent triazole fungicide and consists of two pairs of enantiomers[trans(2 R, 4 R)-, trans(2 S, 4 S)-configurations and cis(2 R, 4 S), cis(2 S, 4 R)-configurations]. The degradation of the enantiomers of(2 RS, 4 RS)-and(2 RS, 4 SR)-bromuconazole by phase I metabolism was investigated using rat, mouse, rabbit, dog and human liver microsomes. Bromuconazole isomers were quantified using HPLC-MS/MS(ESI+) after the separation on a combination of a reversed phase and a chiral analytical column. Moreover, the absolute configuration of four enantiomers had been determined based on the comparisons of the vibrational circular dichroism experimental spectra with the theoretical curve obtained by density functional theory calculations. The degradation of all four isomers followed first-order kinetics and the(2 R, 4 S)-bromuconazole displayed a significantly longer half-life during microsomal incubation than that of other antipodes. Moreover the metabolic rates of four isomers in human and mouse were much slower than those in rat, rabbit and dog, indicating species-specific differences in the metabolism of bromuconazole. The Vmax values for(2 S, 4 R)-bromuconazole were obviously higher than those of its antipode in all liver microsomes studied. The Vmax values for(2 R,4 R)-bromuconazole were significantly higher than those for(2 S, 4 S)-bromuconazole in all liver microsomes studied except human.

关 键 词：糠菌唑 对映体 肝微粒体 选择性降解 种属差异 

分 类 号：O657.7[理学—分析化学] S481.1[理学—化学]