Environmental and Food Safety Research Group (SAMA-UV), Desertification Research Centre CIDE (CSIC-UV-GV), Faculty of Pharmacy, University of Valencia, Av. Vicent Andrés Estellés s/n, Burjassot, 46100, Valencia, Spain.
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
Sci Rep. 2017 Nov 17;7(1):15777. doi: 10.1038/s41598-017-15585-1.
European legislation focusing on water quality is expected to broaden to encompass several pharmaceuticals as priority hazardous substances. This manuscript aims to challenge current regulatory approaches that do not recognize stereochemistry of chiral pharmaceuticals by testing the hypothesis that environmental transformation and effects of chiral pharmaceuticals are stereoselective. Our experiments revealed that, while degradation of chiral fluoxetine (FL) in river water occurs via non-enantioselective photochemical and mildly-enantioselective microbial processes favoring the (R)-enantiomer, a pronounced enantioselectivity favoring (S)-FL (leading to the formation of (S)-NFL (norfluoxetine)) is observed during activated sludge treatment. Toxicity tests proved strong enantiomer-specific toxicity in the case of Tetrahymena thermophila, protozoa that are utilized during activated sludge treatment ((R)-FL is 30× more toxic than (S)-FL; (S)-NFL is 10× more toxic than (S)-FL). This is of paramount importance as preferential degradation of (S)-FL in activated sludge microcosms leads to the enrichment of FL with 30× more toxic (R)-FL and formation of 10× more toxic (S)-NFL. It is commonly assumed that a decreased concentration of FL leads to decreased biological impact. Our study proves that despite the overall decrease in FL concentration, accumulation of toxic (R)-FL and formation of toxic (S)-NFL leads to much higher than presumed toxicological effects.
欧洲的水质法规预计将扩大范围，将几种药物纳入优先危险物质。本文旨在通过测试药物环境转化和作用具有立体选择性的假设，挑战目前不承认手性药物立体化学的监管方法。我们的实验表明，尽管手性氟西汀（FL）在河水中的降解是通过非对映选择性光化学和微生物过程进行的，有利于（R）-对映体，但在活性污泥处理过程中，（S）-FL（导致（S）-NFL（去甲氟西汀）的形成）的立体选择性明显有利于（S）-FL。毒性测试证明了在嗜热四膜虫（Tetrahymena thermophila）中的对映体特异性毒性，嗜热四膜虫是在活性污泥处理中使用的原生动物，（R）-FL 的毒性比（S）-FL 高 30 倍；（S）-NFL 的毒性比（S）-FL 高 10 倍。这一点至关重要，因为（S）-FL 在活性污泥微环境中的优先降解会导致 FL 中（R）-FL 的毒性增加 30 倍，（S）-NFL 的毒性增加 10 倍。人们普遍认为 FL 浓度的降低会导致生物影响降低。我们的研究证明，尽管 FL 浓度总体下降，但有毒的（R）-FL 的积累和有毒的（S）-NFL 的形成导致的毒性作用远高于预期。
