Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
Department of Surgery and Anaesthesiology of Domestic Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
Arch Toxicol. 2017 Feb;91(2):699-712. doi: 10.1007/s00204-016-1710-2. Epub 2016 Apr 21.
Crossover animal trials were performed with intravenous and oral administration of deoxynivalenol-3-β-D-glucoside (DON3G) and deoxynivalenol (DON) to broiler chickens and pigs. Systemic plasma concentrations of DON, DON3G and de-epoxy-DON were quantified using liquid chromatography-tandem mass spectrometry. Liquid chromatography coupled to high-resolution mass spectrometry was used to unravel phase II metabolism of DON. Additionally for pigs, portal plasma was analysed to study presystemic hydrolysis and metabolism. Data were processed via tailor-made compartmental toxicokinetic models. The results in broiler chickens indicate that DON3G is not hydrolysed to DON in vivo. Furthermore, the absolute oral bioavailability of DON3G in broiler chickens was low (3.79 ± 2.68 %) and comparable to that of DON (5.56 ± 2.05 %). After PO DON3G administration to pigs, only DON was detected in plasma, indicating a complete presystemic hydrolysis of the absorbed fraction of DON3G. However, the absorbed fraction of DON3G, recovered as DON, was approximately 5 times lower than after PO DON administration, 16.1 ± 5.4 compared with 81.3 ± 17.4 %. Analysis of phase II metabolites revealed that biotransformation of DON and DON3G in pigs mainly consists of glucuronidation, whereas in chickens predominantly conjugation with sulphate occurred. The extent of phase II metabolism is notably higher for chickens than for pigs, which might explain the differences in sensitivity of these species to DON. Although in vitro studies demonstrate a decreased toxicity of DON3G compared with DON, the species-dependent toxicokinetic data and in vivo hydrolysis to DON illustrate the toxicological relevance and consequently the need for further research to establish a tolerable daily intake.
交叉动物试验通过静脉内和口服给予脱氧雪腐镰刀菌烯醇-3-β-D-葡萄糖苷(DON3G)和脱氧雪腐镰刀菌烯醇(DON)进行,采用液相色谱-串联质谱法定量检测 DON、DON3G 和去环氧-DON 的系统血浆浓度。采用液相色谱-高分辨质谱联用技术来揭示 DON 的 II 相代谢。此外,还对猪进行门静脉血浆分析,以研究前体水解和代谢。数据通过定制的房室毒代动力学模型进行处理。鸡的结果表明 DON3G 不会在体内水解为 DON。此外,DON3G 在肉鸡中的口服生物利用度很低(3.79±2.68%),与 DON 的生物利用度(5.56±2.05%)相当。PO 给予 DON3G 后,猪血浆中仅检测到 DON,表明吸收的 DON3G 完全在前体水解。然而,作为 DON 回收的吸收部分的 DON3G 约为 PO 给予 DON 后的 5 倍,16.1±5.4 与 81.3±17.4 相比。对 II 相代谢物的分析表明,DON 和 DON3G 在猪中的生物转化主要包括葡萄糖醛酸化,而在鸡中主要发生硫酸盐结合。鸡的 II 相代谢程度明显高于猪,这可能解释了这些物种对 DON 敏感性的差异。尽管体外研究表明 DON3G 的毒性比 DON 降低,但物种依赖性的毒代动力学数据和体内水解为 DON 说明了其毒理学相关性,因此需要进一步研究以建立可耐受的每日摄入量。