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Toxicol In Vitro. 2017 Jun;41:114-122. doi: 10.1016/j.tiv.2017.02.023. Epub 2017 Mar 1.

Development of a common carp (Cyprinus carpio) pregnane X receptor (cPXR) transactivation reporter assay and its activation by azole fungicides and pharmaceutical chemicals.

Author information

1
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom. Electronic address: a.lange@exeter.ac.uk.
2
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom. Electronic address: J.F.Corcoran@exeter.ac.uk.
3
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Department of Basic Biology, School of Life Science, SOKENDAI (Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan. Electronic address: miyagawa@wakayama-med.ac.jp.
4
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Department of Basic Biology, School of Life Science, SOKENDAI (Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan. Electronic address: taisen@nibb.ac.jp.
5
AstraZeneca, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, Devon TQ5 8BA, United Kingdom. Electronic address: M.Winter@exeter.ac.uk.
6
University of Exeter, Biosciences, College of Life & Environmental Sciences, Exeter EX4 4QD, United Kingdom. Electronic address: C.R.Tyler@exeter.ac.uk.

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.

KEYWORDS:

Azole fungicides; Common carp; Human; Pharmaceuticals; Pregnane X receptor; Transient transactivation assay

PMID:
28259787
PMCID:
PMC5484788
DOI:
10.1016/j.tiv.2017.02.023
[Indexed for MEDLINE]
Free PMC Article

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