Abstract
At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.
Highlights
The study of pharmaceuticals and personal care products (PPCPs) in the environment has prompted significant attention due to their potential for inducing both short and long-term biological effects in aquatic organisms [1]. As these compounds are designed to act on specific therapeutic targets in humans [2], that are often conserved across vertebrate phyla, it is possible that inducible effects demonstrated in human target systems may induce similar effects in non-target organisms, such as fish [3, 4]
As in vitro studies with fish hepatic models can be used to support screening-level bioaccumulation assessment of contaminants [2, 13, 14, 19], the aims of the present study were as follows: (1) determine the metabolic competency of 3-D liver spheroids prepared from rainbow trout, a recommended regulatory fish species, towards selected environmentally relevant pharmaceuticals; (2) utilise this in vitro data to (a) make predictions on pharmaceutical metabolism in fish based on ‘read-across’ to human metabolism data and (b) calculate intrinsic clearance rates for liver spheroids to compare with values obtained from both fish and human in vitro studies
This in vitro model of fish liver spheroids utilises primary liver cells derived from freshly killed rainbow trout, Oncorhynchus mykiss (Walbaum), supplied from the fish husbandry facility of the AstraZeneca Brixham Environmental Laboratory
Summary
The study of pharmaceuticals and personal care products (PPCPs) in the environment has prompted significant attention due to their potential for inducing both short and long-term biological effects in aquatic organisms [1]. As these compounds are designed to act on specific therapeutic targets (e.g. enzymes, transporters and receptors) in humans [2], that are often conserved across vertebrate phyla, it is possible that inducible effects demonstrated in human target systems may induce similar effects in non-target organisms, such as fish [3, 4]. This work represents an AstraZeneca contribution in kind to the Innovative Medicines Initiative (IMI) under grant agreement no.115735—iPiE: Intelligent led assessment of Pharmaceuticals in the Environment; resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2015-2018) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in kind contribution
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