Bursztyka Julian, Debrauwer Laurent, Perdu Elisabeth, Jouanin Isabelle, Jaeg Jean-Philippe, Cravedi Jean-Pierre
UMR1089 Xénobiotiques, INRA, F-31931 Toulouse, France.
J Agric Food Chem. 2008 Jun 25;56(12):4832-9. doi: 10.1021/jf0728045. Epub 2008 Jun 4.
Vinclozolin is a dicarboxymide fungicide that presents antiandrogenic properties through its two hydrolysis products M1 and M2, which bind to the androgen receptor. Because of the lack of data on the biotransformation of vinclozolin, its metabolism was investigated in vitro in precision-cut rat liver slices and in vivo in male rat using [ (14)C]-vinclozolin. Incubations were performed using different concentrations of substrate, and the kinetics of formation of the major metabolites were studied. Three male Wistar rats were fed by gavage with [ (14)C]-VZ. Urine was collected for 24 h and analyzed by radio-HPLC for metabolic profiling. Metabolite identification was carried out on a LCQ ion trap mass spectrometer. In rat liver slices and in vivo, the major primary metabolite has been identified as 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutyranilide (M5) and was mainly present as glucuronoconjugates. M5 is produced by dihydroxylation of the vinyl group of M2. Other metabolites have been identified as 3-(3,5-dichlorophenyl)-5-methyl-5-(1,2-dihydroxyethyl)-1,3-oxazolidine-2,4-dione (M4), a dihydroxylated metabolite of vinclozolin, which undergoes further conjugation to glucuronic acid, and 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3,4-dihydroxy-butanoic acid (M6), a dihydroxylated metabolite of M1.
乙烯菌核利是一种二羧酰亚胺类杀菌剂，通过其两种水解产物M1和M2呈现抗雄激素特性，这两种产物可与雄激素受体结合。由于缺乏乙烯菌核利生物转化的数据，因此在体外利用精密切割的大鼠肝脏切片以及在体内利用[¹⁴C] - 乙烯菌核利对雄性大鼠进行了其代谢研究。使用不同浓度的底物进行孵育，并研究主要代谢产物的形成动力学。给三只雄性Wistar大鼠经口灌胃给予[¹⁴C] - VZ。收集24小时尿液，通过放射性高效液相色谱法进行代谢谱分析。在LCQ离子阱质谱仪上进行代谢产物鉴定。在大鼠肝脏切片和体内，主要的初级代谢产物已被鉴定为3',5'-二氯-2,3,4-三羟基-2-甲基丁酰苯胺（M5），并且主要以葡萄糖醛酸共轭物的形式存在。M5是由M2的乙烯基双羟基化产生的。其他代谢产物已被鉴定为3-(3,5-二氯苯基)-5-甲基-5-(1,2-二羟基乙基)-1,3-恶唑烷-2,4-二酮（M4），这是乙烯菌核利的一种双羟基化代谢产物，它会进一步与葡萄糖醛酸结合，以及2-[[(3,5-二氯苯基)-氨基甲酰基]氧基]-2-甲基-3,4-二羟基丁酸（M�），这是M1的一种双羟基化代谢产物。
