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CYP3A4 activity reduces the cytotoxic effects of okadaic acid in HepaRG cells

  • Toxicokinetics and Metabolism
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Abstract

The biotoxin okadaic acid (OA), produced by dinoflagellates in marine environment, can accumulate in sponges and shellfish. Consumption of contaminated shellfish induces acute toxic effects such as diarrhea, nausea, vomiting, and abdominal pain. CYP3A4, one of the most important human xenobiotic metabolizing enzymes, is supposed to be involved in the metabolism of OA. Aim of our study was to evaluate the role of CYP3A4 in OA in vitro metabolism as well as in cell cytotoxicity in parallel. Therefore, a metabolic competent HepaRG cell line was exposed to OA with and without addition of the CYP3A4 inhibitor ketoconazole. Without the inhibitor, two mono-hydroxylated metabolites could be identified, whereas in its presence, no metabolites could be detected. Confirmation of the formed metabolites was accomplished by measuring the exact masses and investigating the fragmentation pattern. Data obtained from cytotoxicity assays showed that OA cytotoxicity is reduced when CYP3A4 is active. Thus, hydroxylation appears to be a crucial step for metabolic OA detoxification.

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Acknowledgments

This research was supported by the ANSES within the project TOXCYN [Grant EST-09-58]. Katrin Kittler was supported by a fellowship from the CNRS. We greatly thank Biopredic International for technical advices and support with HepaRG cells supply. We would like to thank Sylvie Huet and Ludovic Le Hégarat for technical help and advices with HepaRG cells as well as Jean Michel Delmas for technical assistance with LTQ-Orbitrap.

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Authors and Affiliations

  1. Fougères Laboratory, ANSES, French Agency for Food, Environmental and Occupational Health Safety, 10B Rue Claude Bourgelat – Javené, CS 40608, 35306, Fougères cedex, France

    Katrin Kittler, Valérie Fessard & Dominique Hurtaud-Pessel

  2. Federal Institute for Materials Research and Testing (BAM), Richard-Willstätter-Straße 11, 12489, Berlin, Germany

    Katrin Kittler & Ronald Maul

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  1. Katrin Kittler
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  2. Valérie Fessard
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  4. Dominique Hurtaud-Pessel
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Correspondence to Dominique Hurtaud-Pessel.

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Kittler, K., Fessard, V., Maul, R. et al. CYP3A4 activity reduces the cytotoxic effects of okadaic acid in HepaRG cells. Arch Toxicol 88, 1519–1526 (2014). https://doi.org/10.1007/s00204-014-1206-x

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  • DOI: https://doi.org/10.1007/s00204-014-1206-x

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