TY - JOUR A1 - Kittler, Katrin A1 - Fessard, V. A1 - Maul, Ronald A1 - Hurtaud-Pessel, D. T1 - CYP3A4 activity reduces the cytotoxic effects of okadaic acid in HepaRG cells N2 - 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. KW - Okadaic acid KW - Cytochrome P-450 KW - Hydroxylation KW - Stability KW - Detoxification KW - Phase I metabolism PY - 2014 U6 - https://doi.org/10.1007/s00204-014-1206-x SN - 0340-5761 SN - 1432-0738 VL - 88 IS - 8 SP - 1519 EP - 1526 PB - Springer CY - Berlin ; Heidelberg [u.a.] AN - OPUS4-31567 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Kittler, Katrin A1 - Hurtaud-Pessel, D. A1 - Maul, Ronald A1 - Kolrep, F. A1 - Fessard, V. T1 - In vitro metabolism of the cyanotoxin cylindrospermopsin in HepaRG cells and liver tissue fractions N2 - No evidence for phase I metabolites of the cyanotoxin cylindrospermopsin (CYN) was given using HepaRG cells and different liver tissue fractions when studying metabolic conversion. Although the application of ketoconazole, a CYP3A4 inhibitor, led to a decreased cytotoxicity of CYN, no metabolites were detected applying high resolution mass spectrometry. Quantification of non-modified CYN led to recovery rates of almost 100%. Consequently, reduction of CYN toxicity in the presence of metabolism inhibiting agents must be attributed to alternative pathways. KW - Cylindrospermopsin KW - Metabolism KW - Liver tissue fractions KW - HepaRG cells KW - LC-HRMS KW - Quantification KW - Cyanotoxin PY - 2016 U6 - https://doi.org/10.1016/j.toxicon.2015.11.007 SN - 0041-0101 SN - 1879-3150 VL - 110 SP - 47 EP - 50 PB - Elsevier CY - Oxford [u.a.] AN - OPUS4-35222 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -