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Toxicol In Vitro. 2016 Jun;33:136-46. doi: 10.1016/j.tiv.2016.02.021. Epub 2016 Mar 5.

Modulation of CYP3A4 activity alters the cytotoxicity of lipophilic phycotoxins in human hepatic HepaRG cells.

Author information

1
ANSES, Fougères Laboratory, Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France. Electronic address: pierre-jean.ferron@anses.fr.
2
ANSES, Fougères Laboratory, Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France.
3
INRA, UMR 1331 TOXALIM, 400 route des Chappes, BP 167, 06903, Sophia-Antipolis, France.
4
ANSES, Fougères Laboratory, Analysis of Residues and Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France.

Abstract

The aim of this study was to investigate (i) the cytotoxic effects of lipophilic phycotoxins, including okadaic acid (OA) and dinophysistoxin-1 and -2 (DTX-1 and DTX-2), pectenotoxin-2 (PTX-2), yessotoxin (YTX), spirolide (SPX), and azaspiracids-1, -2 and -3 (AZA-1, AZA-2 and AZA-3), in human HepaRG cells using a multiparametric high content analysis approach, (ii) the ability of nine lipophilic phycotoxins to act as PXR agonists in a HepG2-PXR cell line, (iii) their potential to induce CYP450 activity, and (iv) the role of CYP3A4 in cytotoxicity induced by lipophilic phycotoxins. Our results indicate that while OA, DTX-1 and DTX-2 activated PXR-dependent transcriptional activity in HepG2 cells, no increase of CYP450 (1A2, 3A4, 2C9, 2C19) activities were observed in HepaRG cell following a 72h treatment with these toxins. Multiparametric analysis showed that OA, DTX-1, DTX-2, and PTX-2 were highly cytotoxic in HepaRG cells; inducing cell loss, activation of caspase-3 and γ-H2AX formation. However, no toxicity was observed for YTX, SPX, and AZAs. Moreover, we found that inhibition of CYP3A4 activity by ketoconazole enhances the toxic effects of OA, DTX-1, DTX-2, and PTX-2 in HepaRG cells. Taken together, these results suggest that CYP3A4-mediated metabolism of some lipophilic phycotoxins decreases their in vitro toxicity.

KEYWORDS:

CYP3A4; Cytotoxicity; Hepatocytes; High content analysis; Phycotoxins

PMID:
26956883
DOI:
10.1016/j.tiv.2016.02.021
[Indexed for MEDLINE]

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