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Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (oncorhynchus mykiss)

Artikel i vetenskaplig tidskrift
Författare Britt Wassmur
Johanna Gräns
Peter Kling
Malin C. Celander
Publicerad i Aquatic Toxicology
Volym 100
Nummer/häfte 1
Sidor 91-100
ISSN 0166-445X
Publiceringsår 2010
Publicerad vid Zoologiska institutionen
Sidor 91-100
Språk en
Länkar dx.doi.org/10.1016/j.aquatox.2010.0...
Ämnesord nuclear receptors, PXR, CYP3A, P-glycoprotein, pharmaceuticals, fish
Ämneskategorier Biologiska vetenskaper, Biofarmaci, Toxikologi, Cell- och molekylärbiologi, Fysiologi

Sammanfattning

The pregnane X receptor (PXR) belongs to the nuclear hormone receptor (NR) superfamily and is commonly described as a xenophore or a pharmacophore, as it can be activated by a wide array of xenobiotics, including numerous pharmaceuticals and other environmental pollutants. The PXR regulates expression of e.g. cytochrome P450 3A (CYP3A) and the P-glycoprotein (P-gp) that are involved in excretion of lipophilic xenobiotics and endobiotics. A full length PXR cDNA was isolated from rainbow trout liver and it was expressed in a descending order of magnitude in liver>intestine>kidney>heart. A rainbow trout PXR reporter assay was developed and a suite of pharmaceuticals and other xenobiotics were screened. However, no specific activation of rainbow trout PXR was observed with the substances tested. Interactions of prototypical PXR agonists on PXR signaling in rainbow trout were further investigated in cells of hepatic origin exposed in vitro and in juvenile rainbow trout exposed in vivo. The rainbow trout hepatoma cell line (RTH-149), displayed 600 times lower expression of CYP3A mRNA, compared to primary cultures of hepatocytes, and did not respond to treatment with either pregnenolone 16-carbonitrile (PCN), ketoconazole (KCZ) or rifampicin (RIF), which implies a non-functional PXR in this cell line. Exposure of hepatocytes to PCN and lithocholic acid (LA), resulted in a weak dose-dependent induction of CYP3A and P-gp mRNA levels, Though, exposure to the higher dose of LA (50 M) decreased PXR mRNA levels. Exposure to dexamethasone (DEX) resulted in a decrease in PXR mRNA, without affecting CYP3A mRNA levels in hepatocytes in vitro. Injections of rainbow trout in vivo with 1 mg/kg LA resulted in a slight (albeit not statistically significant) increase in CYP3A mRNA levels without affecting PXR mRNA levels. Although, injection with 10 mg/kg omeprazole (OME) had no effect on PXR and CYP3A mRNA levels, a 60 % inhibition of CYP3A enzyme activities was evident. A high-throughput in vitro screening of a these chemical used showed that OME and RIF acted as weak CYP3A inhibitors whereas LA and DEX did not affect the CYP3A activity. In contrast, PCN acted as an activator of the CYP3A enzyme activity in vitro. Taken together, these data show that some prototypical PXR agonists weakly affect PXR activation in rainbow trout. Besides, some of these agonists have a stronger effect on the CYP3A catalyst. This study demonstrates the importance of investigation effects of pharmaceuticals on the PXR signaling pathway in non-target animals such as fish.

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