Metabolism of the Marine Phycotoxin PTX-2 and Its Effects on Hepatic Xenobiotic Metabolism: Activation of Nuclear Receptors and Modulation of the Phase I Cytochrome P450

Toxins (Basel). 2017 Jul 5;9(7):212. doi: 10.3390/toxins9070212.

Abstract

PTX-2 is a marine biotoxin frequently found in shellfish that can lead to food intoxication in humans. Information regarding PTX-2 metabolism is scarce, and little is known of its effect on xenobiotic-metabolizing enzymes (XME) or its molecular pathways. The aim of this study was consequently to examine PTX-2 Phase I metabolism using rat and human liver S9 fractions, and also to assess the capability of PTX-2: (i) to modulate the gene expression of a panel of Phase I (CYP450) and II (UGT, SULT, NAT, and GST) enzymes, as well as the Phase III or 0 (ABC and SLCO) transporters in the human hepatic HepaRG cell line using qPCR; (ii) to induce specific CYP450 in HepaRG cells measured by immunolabeling detection and the measurement of the cells' activities; and (iii) to activate nuclear receptors and induce CYP promoter activities in HEK-T and HepG2 transfected cell lines using transactivation and reporter gene assay, respectively. Our results indicate that PTX-2 hydroxylation occurred with both rat and human S9 fractions. Whereas PTX-2 mostly upregulated the gene expression of CYP1A1 and 1A2, no induction of these two CYP activities was observed. Lastly, PTX-2 did not act as an agonist of CAR or PXR. Due to its effects on some key XME, more attention should be paid to possible drug-drug interactions with phycotoxins, especially as shellfish can accumulate several phycotoxins as well as other kinds of contaminants.

Keywords: CYP450; PTX-2; metabolism; nuclear receptors.

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Furans / metabolism*
  • Gene Expression
  • Humans
  • Liver / metabolism*
  • Marine Toxins / metabolism*
  • Membrane Transport Proteins / genetics
  • Pyrans / metabolism*
  • Rats
  • Receptors, Aryl Hydrocarbon / genetics
  • Transferases / genetics
  • Xenobiotics / metabolism

Substances

  • Furans
  • Marine Toxins
  • Membrane Transport Proteins
  • Pyrans
  • Receptors, Aryl Hydrocarbon
  • Xenobiotics
  • Cytochrome P-450 Enzyme System
  • pectenotoxin 2
  • Transferases