<i>In vitro</i>models of xenobiotic metabolism in trout for use in environmental bioaccumulation studies

Uchea, Chibuzor; Sarda, Sunil; Schulz-Utermoehl, Timothy; Owen, Stewart F.; Chipman, Kevin

doi:10.3109/00498254.2012.730644

Cited by 18 publications

(19 citation statements)

References 49 publications

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“…For trout liver, [16–17], direct comparisons of freshly excised tissue; isolated cells in suspension and spheroids in extended culture demonstrated, with some exceptions, that gene expression and transporters in 3-D structures approximate well to the excised tissue. This suggests that the model represents at least some of the aspects of the in vivo situation.…”

Section: Resultsmentioning

confidence: 99%

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

et al. 2017

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“…The working lifetime of different in vitro preparations may differ, and it is possible that 1 system is better suited than another for use with slowly metabolized substances. In this regard, we take special note of the work by Uchea et al [30] which showed that liver spheroids, obtained by culturing trout hepatoctyes for 10 d, exhibit metabolic activity similar to that of freshly isolated cells. Liver spheroids, or a similar system, may be particularly useful for performing in vitro biotransformation assays over very long (hours to days) time periods.…”

Section: Discussionmentioning

confidence: 99%

Comparison of trout hepatocytes and liver S9 fractions as in vitro models for predicting hepatic clearance in fish

Fay

Fitzsimmons

Hoffman

et al. 2016

Enviro Toxic and Chemistry

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Isolated hepatocytes and liver S9 fractions have been used to collect in vitro biotransformation data for fish as a means of improving modeled estimates of chemical bioaccumulation. To date, however, there have been few direct comparisons of these 2 methods. In the present study, cryopreserved trout hepatocytes were used to measure in vitro intrinsic clearance rates for 6 polycyclic aromatic hydrocarbons (PAHs). These rates were extrapolated to estimates of in vivo intrinsic clearance and used as inputs to a well stirred liver model to predict hepatic clearance. Predicted rates of hepatic clearance were then evaluated by comparison with measured rates determined previously using isolated perfused livers. Hepatic clearance rates predicted using hepatocytes were in good agreement with measured values (<2.1-fold difference for 5 of 6 compounds) under 2 competing binding assumptions. These findings, which may be attributed in part to high rates of PAH metabolism, are similar to those obtained previously using data from liver S9 fractions. For 1 compound (benzo[a]pyrene), the in vivo intrinsic clearance rate calculated using S9 data was 10-fold higher than that determined using hepatocytes, possibly due to a diffusion limitation on cellular uptake. Generally, however, there was good agreement between calculated in vivo intrinsic clearance rates obtained using either in vitro test system. These results suggest that both systems can be used to improve bioaccumulation assessments for fish, particularly when vitro rates of activity are relatively high, although additional work is needed to determine if the chemical domain of applicability for each system differs. Environ Toxicol Chem 2017;36:463-471. Published 2016 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

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“…Developing protocols for in vitro biotransformation tests using fish liver is of particular interest because existing bioaccumulation models for fish can use the bioassay data to estimate BCF and BAF values [3][4][5][6]10]. Various fish liver preparations include 9000-g supernatants of liver homogenate (S9) [4,7,8,11], microsomes [6,8], freshly isolated hepatocytes [4,7,12,13], and cultured hepatocytes [13]. Ex vivo assays using isolated perfused fish livers have also been proposed to measure biotransformation rates that can be extrapolated to the whole body [14].…”

Section: Introductionmentioning

confidence: 99%

In vitro biotransformation rates in fish liver S9: Effect of dosing techniques

Lee

Delafoulhouze

et al. 2014

Enviro Toxic and Chemistry

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In vitro biotransformation assays are currently being explored to improve estimates of bioconcentration factors of potentially bioaccumulative organic chemicals in fish. The present study compares thin-film and solvent-delivery dosing techniques as well as single versus multiple chemical dosing for measuring biotransformation rates of selected polycyclic aromatic hydrocarbons in rainbow trout (Oncorhynchus mykiss) liver S9. The findings show that biotransformation rates of very hydrophobic substances can be accurately measured in thin-film sorbent-dosing assays from concentration-time profiles in the incubation medium but not from those in the sorbent phase because of low chemical film-to-incubation-medium mass-transfer rates at the incubation temperature of 13.5 °C required for trout liver assays. Biotransformation rates determined by thin-film dosing were greater than those determined by solvent-delivery dosing for chrysene (octanol-water partition coefficient [KOW ] =10(5.60) ) and benzo[a]pyrene (KOW =10(6.04) ), whereas there were no statistical differences in pyrene (KOW =10(5.18) ) biotransformation rates between the 2 methods. In sorbent delivery-based assays, simultaneous multiple-chemical dosing produced biotransformation rates that were not statistically different from those measured in single-chemical dosing experiments for pyrene and benzo[a]pyrene but not for chrysene. In solvent-delivery experiments, multiple-chemical dosing produced biotransformation rates that were much smaller than those in single-chemical dosing experiments for all test chemicals. While thin-film sorbent-phase and solvent delivery-based dosing methods are both suitable methods for measuring biotransformation rates of substances of intermediate hydrophobicity, thin-film sorbent-phase dosing may be more suitable for superhydrophobic chemicals.

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In vitromodels of xenobiotic metabolism in trout for use in environmental bioaccumulation studies

Cited by 18 publications

References 49 publications

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

Comparison of trout hepatocytes and liver S9 fractions as in vitro models for predicting hepatic clearance in fish

In vitro biotransformation rates in fish liver S9: Effect of dosing techniques

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