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THE PLHC-1 CELL LINE AS A MODEL FOR IDENTIFYING TOXICOKINETIC INTERACTIONS – PROS AND CONS

Conference paper
Authors Britt Wassmur
Johanna Gräns
Marie Michelová
Joanna Wilson
Malin C. Celander
Published in PRIMO 17 conference, Faro, Portugal, May 2013
Publication year 2013
Published at Department of Biological and Environmental Sciences
Language en
Keywords cocktail effects, cytochrome P450, fish
Subject categories Toxicology

Abstract

Many chemicals, with different mode-of-action, share common pathways for metabolism and elimination. This can result in unexpected and adverse toxicokinetic interactions in situations of mixed exposure. Catabolic CYP enzymes and ABC transporters/efflux pumps are typical sites for toxicokinetic interactions. A partial CYP3B-like cDNA was identified in PLHC-1 cells and basal expression was lower than that for CYP1A. The CYP3B-like gene was not inducible by prototypical AhR, GR or PXR agonists and no CYP3A gene has been reported in PLHC-1. Metabolism of the diagnostic CYP3A substrate 7-benzyloxy-4-[trifluoromethyl]-coumarin was lower in PLHC-1 cells than in rainbow trout hepatocytes and liver microsomes. The PLHC-1 cell line is therefore not a suitable model for identifying interactions on PXR-CYP3A signaling. Exposure to the microtubule disrupter nocodazole resulted in weak induction of CYP1A, despite impaired cytoskeleton morphology. Co-exposure of nocodazole and the AhR agonist β-naphthoflavone (BNF) resulted in enhanced and prolonged induction of CYP1A, compared to cells exposed to these chemicals alone. This synergistic induction of CYP1A in cells co-exposed to BNF and nocodazole was likely a result of inhibition of BNF elimination. Both BNF and nocodazole acted as potent inhibitors of the CYP1A activity. Nocodazole also acted as a weak inhibitor of efflux activity, but BNF had no effect on efflux. This suggests that BNF and nocodazole share CYP1A for their metabolic clearance and that they compete for the CYP1A enzyme when they are mixed. The study illustrates that inhibition of CYP1A activity increases the sensitivity to exposure to AhR agonists. The PLHC-1 cell line can be used as a model to identify and determine toxicokinetic interactions on AhR-CYP1A signaling and ABC transporter activities. This can be applied to score individual chemicals in a mixture based on their interactions on these targets in order to assess their biological half-lives in a mixture.

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