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Effects of Pharmaceuticals on the Expression of Genes Involved in Detoxification in a Carp Primary Hepatocyte Model
journal contribution
posted on 2012-06-05, 00:00 authored by Jenna Corcoran, Anke Lange, Matthew
J. Winter, Charles R. TylerFish in many surface freshwaters are exposed to a range
of pharmaceuticals
via wastewater treatment works effluent discharges. In mammals the
pregnane X receptor (PXR) plays a key role in the regulation of a
suite of genes involved in drug biotransformation, but information
on the role of this response pathway in fish is limited. Here we investigated
the effects of exposure of carp (Cyprinus carpio)
primary hepatocytes to the human PXR agonist rifampicin (RIF) on expression
of target genes involved in phase I (cyp2k, cyp3a) and phase II (gstα, gstπ) drug metabolism and drug transporters mdr1 and mrp2. RIF induced expression of
all target genes measured and the PXR antagonist ketoconazole (KET)
inhibited responses of cyp2k and cyp3a. Exposure of the primary carp hepatocytes to the pharmaceuticals
ibuprofen (IBU), clotrimazole (CTZ), clofibric acid (CFA) and propranolol
(PRP), found responses to IBU and CFA, but not CTZ or PRP. This is
in contrast with mammals, where CTZ is a potent PXR-agonist. Collectively
our data indicate potential PXR involvement in regulating selected
genes involved in drug metabolism in fish, but suggest some divergence
in the regulation pathways with those in mammals. The carp primary
hepatocyte model serves as a useful system for screening for responses
in these target genes involved in drug metabolism.