1. Differences in metabolism of the marine biotoxin okadaic acid by human and rat cytochrome P450 monooxygenases.
- Author
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Kolrep F, Hessel S, These A, Ehlers A, Rein K, and Lampen A
- Subjects
- Animals, Cell Culture Techniques, Cell Survival drug effects, Chromatography, High Pressure Liquid, Cytochrome P-450 CYP1A2 genetics, Cytochrome P-450 CYP3A genetics, Hep G2 Cells, Humans, Liver enzymology, Rats, Recombinant Proteins genetics, Recombinant Proteins metabolism, Species Specificity, Tandem Mass Spectrometry, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP3A metabolism, Liver drug effects, Marine Toxins toxicity, Okadaic Acid toxicity
- Abstract
The ingestion of seafood contaminated with the marine biotoxin okadaic acid (OA) can lead to diarrhetic shellfish poisoning with symptoms like nausea, vomiting and abdominal cramps. Both rat and the human hepatic cytochrome P450 monooxygenases (CYP) metabolize OA. However, liver cell toxicity of metabolized OA is mainly unclear. The aim of our study was to detect the cellular effects in HepG2 cells exposed to OA in the presence of recombinant CYP enzymes of both rat and human for the investigation of species differences. The results should be set in correlation with a CYP-specific metabolite pattern. Comparative metabolite profiles of OA after incubation in rat and human recombinant CYP enzymes were established by using LC-MS/MS technique. Results demonstrated that metabolism of OA to oxygenated metabolites correlates with detoxification which was mainly catalyzed by human CYP3A4 and CYP3A5. Detoxification by rat Cyp3a1 was lower compared to human CYP3A enzymes and activation of OA by Cyp3a2 was observed, coincident with minor overall conversion capacity of OA. By contrast human and rat CYP1A2 seem to activate OA into cytotoxic intermediates. In conclusion, different mechanisms of OA metabolism may occur in the liver. At low OA doses, the human liver is likely well protected against cytotoxic OA, but for high shellfish consumers a potential risk cannot be excluded.
- Published
- 2016
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