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

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 gamma-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.
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Toxicology in vitro : an international journal published in association with BIBRA, 2016, 33, pp.136-146. 〈http://www.sciencedirect.com/science/article/pii/S088723331630025X〉. 〈10.1016/j.tiv.2016.02.021〉
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https://hal-anses.archives-ouvertes.fr/anses-01340742
Contributeur : Emmanuelle Chiffoleau <>
Soumis le : vendredi 1 juillet 2016 - 16:38:55
Dernière modification le : jeudi 11 janvier 2018 - 17:01:59

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Pierre-Jean Ferron, Kevin Hogeveen, Georges De Sousa, R. Rahmanifard, Estelle Dubreil-Cheneau, et al.. Modulation of CYP3A4 activity alters the cytotoxicity of lipophilic phycotoxins in human hepatic HepaRG cells. Toxicology in vitro : an international journal published in association with BIBRA, 2016, 33, pp.136-146. 〈http://www.sciencedirect.com/science/article/pii/S088723331630025X〉. 〈10.1016/j.tiv.2016.02.021〉. 〈anses-01340742〉

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