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

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

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.

MeSH terms

  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Line
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • DNA Damage
  • Furans / toxicity
  • Histones / metabolism
  • Humans
  • Ketoconazole / pharmacology
  • Liver / cytology
  • Marine Toxins / toxicity
  • Okadaic Acid / toxicity
  • Oxocins / toxicity
  • Pyrans / toxicity
  • Spiro Compounds / toxicity

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Furans
  • H2AX protein, human
  • Histones
  • Marine Toxins
  • Oxocins
  • Pyrans
  • Spiro Compounds
  • Okadaic Acid
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Caspase 3
  • Ketoconazole