Abstract
In mammals, the pregnane X receptor (PXR) is a transcription factor with a key role in regulating expression of several genes involved in drug biotransformation. PXR is present in fish and some genes known to be under its control can be up-regulated by mammalian PXR ligands. Despite this, direct involvement of PXR in drug biotransformation in fish has yet to be established. Here, the full length PXR sequence was cloned from carp (Cyprinus carpio) and used in a luciferase reporter assay to elucidate its role in xenobiotic metabolism in fish. A reporter assay for human PXR (hPXR) was also established to compare transactivation between human and carp (cPXR) isoforms. Rifampicin activated hPXR as expected, but not cPXR. Conversely, clotrimazole (CTZ) activated both isoforms and was more potent on cPXR, with an EC50 within the range of concentrations of CTZ measured in the aquatic environment. Responses to other azoles tested were similar between both isoforms. A range of pharmaceuticals tested either failed to activate, or were very weakly active, on the cPXR or hPXR. Overall, these results indicate that the cPXR may differ from the hPXR in its responses and/or sensitivity to induction by different environmental chemicals, with implications for risk assessment because of species differences.
Highlights
Aquatic species may be exposed to a wide range of xenobiotic compounds present in the environment, including human pharmaceuticals and personal care products
Sequence analyses showed that carp pregnane X receptor (PXR) (cPXR) has a highly conserved DNA binding domain (DBD) consisting of two C4-type zinc fingers and including a P-box motif (CEGCKG; a sequence essential for DNA-binding specificity) and a conserved ligand-binding domain (LBD) including the AF-2 motif (PLxxEx), essential for co-regulator interaction during ligand binding of transcription factors
The percent identities of the cPXR DBD and LBD reported here are in agreement with those published for other fish species, including the zebrafish, another cyprinid species (Bainy et al, 2013; Krasowski et al, 2005; Milnes et al, 2008)
Summary
Aquatic species may be exposed to a wide range of xenobiotic compounds present in the environment, including human pharmaceuticals and personal care products. Pregnenolone 16α-carbonitrile (PCN) activates the PXR in rodents, but shows a much reduced activity on human or rabbit PXR (Blumberg et al, 1998; Jones et al, 2000; Lehmann et al, 1998; Savas et al., 2000) The basis for this divergence is thought to be due to differences in the amino acid sequences in the ligand binding domain (Kliewer et al, 2002). As a result this variability in detoxification efficiency is likely to be reflected in the ability of different species groups to successfully process xenobiotics encountered in the environment
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