Ibuprofen Metabolism in the Liver and Gill of Rainbow Trout, Oncorhynchus mykiss

Abstract

The presence of pharmaceuticals in the environment has become an important topic of discussion with respect to pharmaceutical absorption, metabolism and elimination in fish. This study investigates the metabolism of ibuprofen by rainbow trout (Oncorhynchus mykiss). In vitro metabolic loss of parent compound was measured in gill and liver S9 and microsomal fractions. Metabolite analysis found 2-hydroxy-ibuprofen as the major metabolite in uninduced S9 fractions. Supplementing S9 fractions with UDPGA did not significantly enhance metabolism. Additionally, assays involving the induction and inhibition of specific CYP isozymes support CYP1A2 as a possible metabolic pathway in fish.

Sub-lethal effects induced by a mixture of three non-steroidal anti-inflammatory drugs (NSAIDs) on the freshwater bivalve Dreissena polymorpha

“…Lastly, IBU is readily metabolised through phase I and phase II pathways; in human and rat liver, CYP 450 isoforms contribute to the majority of its phase I biotransformation (Jacqz-Aigrain and Anderson 2006). Accordingly, there is also evidence of the formation of CYP-induced metabolites of DCF (Mehinto et al 2010), IBU (Gomez et al 2011) and PCM (Huber et al 2009) in non-target species. Considering that several isoforms or encoding gene sequences of CYP 450 belonging to the 2, 4 and 6 families have been described in mussels (Chaty et al 2004), the activation of zebra mussel phase I enzyme complex could produce reactive metabolites of the tested NSAIDs.…”

Effects of pharmaceuticals present in aquatic environment on Phase I metabolism in fish

“…Previous studies indicate that NSAIDs have effects on fish at environmentally relevant concentrations (Saravanan and Ramesh, 2013) and caused adverse histopathological changes in various tissues of many species (Hoeger et al, 2005;Mehinto et al, 2010;Memmert et al, 2013;Schwaiger et al, 2004) at higher concentrations. Metabolites of naproxen and ibuprofen have been identified in bile as well as in gill and hepatic S9 fractions, respectively, of rainbow trout (Brozinski et al, 2011;Gomez et al, 2011). These metabolites can be produced by fish hepatic metabolism.…”

“…These metabolites can be produced by fish hepatic metabolism. One possible metabolic pathway of ibuprofen in fish can be through the CYP1A1 and CYP1A2 isozymes (Gomez et al, 2011;Thibaut and Porte, 2008). EROD activity in hepatic microsomes was induced inDicentrarchuslabrax and inhibited inTrachyrincusscabrus,…”

“…Moreover, diclofenac inhibited piscine CYP3A-, CYP11B-and CYP17-mediated reactions (Gomez et al, 2011;Ribalta and Sole, 2014). Most research on pharmaceutical metabolism so far has been focused on Phase I reactions.…”

In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes?

“…For example, from an environmental perspective, if a substance is suspected to have effects on a fish species, then the use of a fish liver S9 system may be most appropriate. Recent sources of fish S9 are described in Han et al (2009) and Gomez et al (2011). Trout S9 fractions have been used as metabolic "activating" systems in different assays such as logical variability, a potential solution is a concordance analysis with assays for the same endpoints, both in vitro and then in vivo where data already exists, or for subsequent in vivo screening and test prioritization purposes (e.g., ER binding assays first with estrogen proliferation assays and ER reporter gene assays, and then with uterotrophic assay) to discern whether any respond with sufficient precision to allow biologically significant changes to be identified and thus inform the AOP.…”