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Toxins (Basel). 2017 Jul 5;9(7). pii: E212. doi: 10.3390/toxins9070212.

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.

Author information

1
Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, 35306 Fougères, France. jimmy.alarcan@anses.fr.
2
Analysis of Residues and Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, 35306 Fougères, France. estelle.dubreil@anses.fr.
3
Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, 35306 Fougères, France. antoine.huguet@anses.fr.
4
Analysis of Residues and Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, 35306 Fougères, France. dominique.pessel@anses.fr.
5
Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany. Stefanie.Hessel-Pras@bfr.bund.de.
6
Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany. Alfonso.Lampen@bfr.bund.de.
7
Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, 35306 Fougères, France. valerie.fessard@anses.fr.
8
Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, ANSES, 35306 Fougères, France. ludovic.lehegarat@anses.fr.

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

PMID:
28678150
PMCID:
PMC5535159
DOI:
10.3390/toxins9070212
[Indexed for MEDLINE]
Free PMC Article

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