Gene expression profiling of human liver carcinoma (HepG2) cells exposed to the marine toxin okadaic acid

Fieber, Lynne A.; Greer, Justin B.; Guo, Fujiang; Crawford, Douglas L.; Rein, Kathleen S.

doi:10.1080/02772248.2012.730199

Cited by 8 publications

(1 citation statement)

References 72 publications

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“…Thus, Ishida et al [ 66 ] found different cell cycle arrest in myeloid leukemic cells, either at G 1 /S phase or at G 2 /M phase, depending on the OA dose. Recently, Fieber et al [ 75 ] also observed that OA stimulates genes involved in the cell cycle progress at low concentrations whereas it promotes apoptosis at high concentrations. These results support the previous ones in which OA was found to induce mitotic arrest, followed by apoptosis in a synchronized manner [ 67 ].…”

Section: Oa Beyond Its Role As Dsp Inductormentioning

confidence: 99%

Okadaic Acid: More than a Diarrheic Toxin

et al. 2013

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Okadaic acid (OA) is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases and a tumor promoter in animal carcinogenesis experiments. In the last few decades, the potential toxic effects of OA, beyond its role as a DSP toxin, have been investigated in a number of studies. Alterations in DNA and cellular components, as well as effects on immune and nervous system, and even on embryonic development, have been increasingly reported. In this manuscript, results from all these studies are compiled and reviewed to clarify the role of this toxin not only as a DSP inductor but also as cause of alterations at the cellular and molecular levels, and to highlight the relevance of biomonitoring its effects on human health. Despite further investigations are required to elucidate OA mechanisms of action, toxicokinetics, and harmful effects, there are enough evidences illustrating its toxicity, not related to DSP induction, and, consequently, supporting a revision of the current regulation on OA levels in food.

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Section: Oa Beyond Its Role As Dsp Inductormentioning

confidence: 99%

Okadaic Acid: More than a Diarrheic Toxin

et al. 2013

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Differences in metabolism of the marine biotoxin okadaic acid by human and rat cytochrome P450 monooxygenases

et al. 2015

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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.

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A multi-omics approach to elucidate okadaic acid-induced changes in human HepaRG hepatocarcinoma cells

Wuerger,

Sprenger,

Krasikova

et al. 2024

Arch Toxicol

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Okadaic acid (OA), a prevalent marine biotoxin found in shellfish, is known for causing acute gastrointestinal symptoms. Despite its potential to reach the bloodstream and the liver, the hepatic effects of OA are not well understood, highlighting a significant research gap. This study aims to comprehensively elucidate the impact of OA on the liver by examining the transcriptome, proteome, and phosphoproteome alterations in human HepaRG liver cells exposed to non-cytotoxic OA concentrations. We employed an integrative multi-omics approach, encompassing RNA sequencing, shotgun proteomics, phosphoproteomics, and targeted DigiWest analysis. This enabled a detailed exploration of gene and protein expression changes, alongside phosphorylation patterns under OA treatment. The study reveals concentration- and time-dependent deregulation in gene and protein expression, with a significant down-regulation of xenobiotic and lipid metabolism pathways. Up-regulated pathways include actin crosslink formation and a deregulation of apoptotic pathways. Notably, our results revealed that OA, as a potent phosphatase inhibitor, induces alterations in actin filament organization. Phosphoproteomics data highlighted the importance of phosphorylation in enzyme activity regulation, particularly affecting proteins involved in the regulation of the cytoskeleton. OA's inhibition of PP2A further leads to various downstream effects, including alterations in protein translation and energy metabolism. This research expands the understanding of OA's systemic impact, emphasizing its role in modulating the phosphorylation landscape, which influences crucial cellular processes. The results underscore OA's multifaceted effects on the liver, particularly through PP2A inhibition, impacting xenobiotic metabolism, cytoskeletal dynamics, and energy homeostasis. These insights enhance our comprehension of OA's biological significance and potential health risks.

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Gene expression profiling of human liver carcinoma (HepG2) cells exposed to the marine toxin okadaic acid

Cited by 8 publications

References 72 publications

Okadaic Acid: More than a Diarrheic Toxin

Okadaic Acid: More than a Diarrheic Toxin

Differences in metabolism of the marine biotoxin okadaic acid by human and rat cytochrome P450 monooxygenases

A multi-omics approach to elucidate okadaic acid-induced changes in human HepaRG hepatocarcinoma cells

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