Ecotoxicological properties of ketoprofen and the S(+)‐enantiomer (dexketoprofen): Bioassays in freshwater model species and biomarkers in fish PLHC‐1 cell line

The increased use of non-steroidal anti-inflammatory drugs (NSAIDs) has resulted in their ubiquitous presence in the environment. The toxicological properties of these two widely prescribed NSAIDs, namely - racemic ketoprofen (rac-KP) and its enantiomer S(+)-ketoprofen (dexketoprofen, DKP) were evaluated. Firstly, by acute and chronic toxicity tests using three representative model organisms (Vibrio fischeri, Pseudokirchneriella subcapitata and Ceriodaphnia dubia). Secondly, by evaluating the responses of biotransformation systems and multidrug resistance associated proteins (MRP1/MRP2) using the PLHC-1 fish hepatic cell-line. Toxicity data from both acute and chronic DKP exposure indicated higher sensitivity through inhibition of bioluminescence and algal growth and through increased mortality/immobilization compared to rac-KP exposure. The growth inhibition test showed that rac-KP and DKP exhibited different values for EC50 (240.2 µg/L and 65.6 µg/L, respectively). Furthermore, rac-KP and DKP did not exert cytotoxic effects in PLHC-1 cells, and produced compound-, time- and concentration-specific differential effects on CYP1A and GST levels. For CYP1A, the effects of rac-KP and DKP differed at transcriptional and catalytic level. Exposure to rac-KP and DKP modulated MRP1 and MRP2 mRNA levels and these effects were also dependent on compound, exposure time and concentration of the individual drug. The present study revealed for the first time, the interactions between these NSAIDs and key detoxification systems, and different sensitivity to the racemic mixture compared to its enantiomer. This article is protected by copyright. All rights reserved.