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

• Published in: Toxicology in vitro Vol. 33; pp. 136 - 146
• Main Authors: Ferron, P.J., Hogeveen, K., De Sousa, G., Rahmani, R., Dubreil, E., Fessard, V., Le Hegarat, L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2016; Elsevier
• Subjects: Apoptosis - drug effects; Caspase 3 - metabolism; Cell Line; CYP3A4; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Cytotoxicity; DNA Damage; Furans - toxicity; Hepatocytes; High content analysis; Histones - metabolism; Humans; Ketoconazole - pharmacology; Life Sciences; Liver - cytology; Marine Toxins - toxicity; Okadaic Acid - toxicity; Oxocins - toxicity; Phycotoxins; Pyrans - toxicity; Spiro Compounds - toxicity; Toxicology; Cytotoxicity; Phycotoxins; High content analysis; Hepatocytes; CYP3A4; toxicity; toxicology; toxicité; phycotoxin; cellule humaine hépatique; cellule HepaRG; HepaRG cell; toxicologie; human hepatic cell; phycotoxine; cytotoxicity; cytotoxicité
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2016.02.021

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.
•Liphophilic phycotoxins induced caspase-3 activation and γH2AX on human HepaRG cells.•Inhibition of CYP3A4 increased toxic effect of toxins in HepaRG cells.•Okadaic acid, dinophysistoxin-1 and 2 induced PXR activation in HepG2-PXR cell lines.•Lipophilic phycotoxins did not induced cytochrome P450 activities in HepaRG cells.