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.

Jimmy Alarcan,Ludovic Le Hegarat,Valérie Fessard,Antoine Huguet,Estelle Dubreil,Dominique Hurtaud-Pessel,Alfonso Lampen,Stefanie Hessel-Pras

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.

Highlights

Pectenotoxins (PTXs) are a group of marine biotoxins whose structure is based on polyether lactones produced by a restricted variety of phytoplanktonic species [1,2,3]
We compared the metabolism of PTX-2 by human and rat liver S9 fractions, and we investigated the capability of PTX-2: (i) to modulate the gene expression of a panel of Phase I
9, 212 could be 2017, found (Figure 2a,b). Since these data strongly suggest a major role for Phase I enzymes in the metabolism of PTX-2, we. Since these data strongly suggest a major role for Phase I enzymes in the metabolism of PTX-2, investigated whether PTX-2 may modulate xenobiotic-metabolizing enzyme (XME) gene expressions we investigated whether PTX-2 may modulate xenobiotic-metabolizing enzyme (XME) gene in liver cells such as the metabolic competent expressions in liver cells such as the metabolic HepaRG

Summary

Introduction

Pectenotoxins (PTXs) are a group of marine biotoxins whose structure is based on polyether lactones produced by a restricted variety of phytoplanktonic species [1,2,3]. Among this group, pectenotoxin 2 (PTX-2, see Figure 1) is the best documented compound. Toxins 2017, 9, 212 hepatic damage after intraperitoneal injection [7]. We previously showed that PTX-2 was cytotoxic in the human metabolic competent hepatoma cell line HepaRG, inducing apoptosis and DNA damage [11]. We showed that PTX-2 failed to induce PXR translocation in HepG2 cells [11]

Objectives

Methods

Results

Discussion

Conclusion