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Arch Toxicol. 2014 Aug;88(8):1519-26. doi: 10.1007/s00204-014-1206-x. Epub 2014 Feb 7.

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

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

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.

PMID:
24504163
[PubMed - in process]
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