Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Box 430, SE-405 30 Göteborg, Sweden.
Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Box 440, SE-405 30 Göteborg, Sweden.
Sci Total Environ. 2015 Apr 1;511:37-46. doi: 10.1016/j.scitotenv.2014.12.016. Epub 2014 Dec 18.
Asthma is commonly treated with inhalable glucocorticosteroids, including beclomethasone dipropionate (BDP). This is a synthetic prodrug which is metabolized to the more active monopropionate (BMP) and free beclomethasone in humans. To evaluate potential effects of residual drugs on fish, we conducted a 14 day flow-through exposure experiment with BDP and beclomethasone using rainbow trout, and analyzed effects on plasma glucose, hepatic glutathione and catalase activity together with water and body concentrations of the BDP, BMP and beclomethasone. We also analyzed hepatic gene expression in BDP-exposed fish by microarray and quantitative PCR. Beclomethasone (up to 0.65 μg/L) was not taken up in the fish while BDP (0.65 and 0.07 μg/L) resulted in accumulation of both beclomethasone, BMP and BDP in plasma, reaching levels up to those found in humans during therapy. Accordingly, exposure to 0.65 μg/L of BDP significantly increased blood glucose as well as oxidized glutathione levels and catalase activity in the liver. Exposure to beclomethasone or the low concentration of BDP had no effect on these endpoints. Both exposure concentrations of BDP resulted in significantly higher transcript abundance of phosphoenolpyruvate carboxykinase involved in gluconeogenesis, and of genes involved in immune responses. As only the rapidly metabolized prodrug was potent in fish, the environmental risks associated with the use of BDP are probably small. However, the observed physiological effects in fish of BDP at plasma concentrations known to affect human physiology provides valuable input to the development of read-across approaches in the identification of pharmaceuticals of environmental concern.
哮喘通常采用吸入性糖皮质激素治疗，包括丙酸倍氯米松（BDP）。这是一种合成前药，在人体中代谢为更活跃的单丙酸酯（BMP）和游离倍氯米松。为了评估残留药物对鱼类的潜在影响，我们用虹鳟鱼进行了为期 14 天的 BDP 和倍氯米松流动暴露实验，分析了对血浆葡萄糖、肝谷胱甘肽和过氧化氢酶活性的影响，以及 BDP、BMP 和倍氯米松在水中和体内的浓度。我们还通过微阵列和定量 PCR 分析了 BDP 暴露鱼类的肝基因表达。贝美莫司（最高 0.65μg/L）未被鱼类吸收，而 BDP（0.65 和 0.07μg/L）导致贝美莫司、BMP 和 BDP 在血浆中积累，达到治疗期间人类发现的水平。因此，暴露于 0.65μg/L 的 BDP 显著增加了血糖以及肝中氧化型谷胱甘肽水平和过氧化氢酶活性。暴露于贝美莫司或低浓度的 BDP 对这些终点没有影响。BDP 的两种暴露浓度均导致参与糖异生的磷酸烯醇丙酮酸羧激酶和参与免疫反应的基因的转录丰度显著增加。由于只有快速代谢的前药在鱼类中有效，因此与使用 BDP 相关的环境风险可能很小。然而，在已知影响人类生理学的血浆浓度下，BDP 对鱼类的观察到的生理影响为识别环境关注的药物提供了有价值的信息，有助于建立同类药物推断方法。
