Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis

Luckert, Claudia; Hessel, Stefanie; Lenze, Dido; Lampen, Alfonso

doi:10.1016/j.tiv.2015.06.021

Cited by 33 publications

(29 citation statements)

References 57 publications

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“…Concerning PA pharmacokinetics, after oral ingestion these compounds are absorbed from the gastrointestinal tract [ 25 ]. Most of them, around 80%, are excreted in urine, feces and milk, a few being able to pass the placenta due to their high lipophilicity [ 25 , 26 , 27 ]. Bioactivation occurs mostly in the liver and, for this reason, this organ is the most affected by toxicity [ 28 ].…”

Section: Biological Activity Of Pamentioning

confidence: 99%

“…In 1954, Schoental et al discovered that retrorsine was capable of inducing tumors in experimental studies in animals [ 30 , 62 ]. Tumors developed in liver, lung, bladder, skin, brain, spinal cord, pancreas and gastrointestinal tract were found [ 25 ]. All PA known to have this effect belong to heliotridine-, retronecine- and otonecine-types.…”

Section: Toxicitymentioning

confidence: 99%

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Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety

Moreira

Pereira

Valentão

2018

IJMS

201

180

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Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA.

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Section: Biological Activity Of Pamentioning

confidence: 99%

Section: Toxicitymentioning

confidence: 99%

Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety

Moreira

Pereira

Valentão

2018

IJMS

201

180

View full text Add to dashboard Cite

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“…Previous studies demonstrate an influence of PAs on the induction of apoptosis in different in vivo and in vitro models . However, it is not clear from these studies whether the observed apoptotic pathway followed intrinsic or extrinsic signals.…”

Section: Introductionmentioning

confidence: 89%

“…However, the molecular mechanisms of toxicity are not well understood until now. Previous studies with rats and in vitro liver cell models indicate PA‐mediated induction of apoptosis in hepatocytes …”

Section: Introductionmentioning

confidence: 98%

Sensitization of Human Liver Cells Toward Fas‐Mediated Apoptosis by the Metabolically Activated Pyrrolizidine Alkaloid Lasiocarpine

Ebmeyer

Franz

Lim

et al. 2019

Molecular Nutrition Food Res

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Scope: Pyrrolizidine alkaloids (PAs) are common phytotoxins. Intoxication can lead to liver damage. Previous studies showed PA-induced apoptosis in liver cells. However, the exact role of the extrinsic apoptotic pathway has not been investigated yet. This study aims to analyze whether the PA representative lasiocarpine sensitizes human liver cells toward extrinsic Fas-mediated apoptosis. Methods and results: HepG2 cells with limited xenobiotic metabolic activity are used to analyze metabolism-dependent effects. External in vitro metabolism is simulated using rat or human liver enzymes. Additionally, metabolically competent HepaRG cells are used to confirm the observed effects in a human liver cell system with internal xenobiotic metabolism. Metabolized lasiocarpine decreases cell viability and induces Fas receptor gene expression in both cell lines. Increased Fas receptor protein expression on the cell surface is demonstrated by flow cytometry. The addition of a Fas ligand-simulating antibody induces apoptosis. Induction of extrinsicFas-mediated apoptosis is verified by Western blotting for cleaved caspase 8, the initiator caspase of extrinsic apoptosis. All effects are dependent on lasiocarpine metabolism. Conclusion: The results demonstrate that metabolically metabolized lasiocarpine sensitizes human liver cells toward Fas-mediated apoptosis. They broaden our knowledge on the hepatotoxic molecular mechanisms of PA as widely distributed food contaminants.

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“…Numerous publications have successfully demonstrated that transcriptomics are suitable to distinguish genotoxic from non-genotoxic carcinogens (Lee et al, 2013;Magkoufopoulou, Claessen, Jennen, Kleinjans, & van Delft, 2011;Mathijs et al, 2009). Additional effort has been undertaken to use omics data to define specific biological functions or pathways which are connected to cellular responses to genotoxins, often using liver cells as a model system due to the need of metabolic activation of many genotoxic compounds: for example, deregulation of genes related to cell cycle and proliferation (Luckert, Hessel, Lenze, & Lampen, 2015;Rieswijk et al, 2016), apoptosis and cell death (Luckert et al, 2015;van Kesteren et al, 2011), and/or cellular and oxidative stress (Deferme, Wolters, Claessen, Briede, & Kleinjans, 2015;Smit, Souza, Jennen, Kleinjans, & van den Beucken, 2017) have been reported in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic effect marker patterns of genotoxins – a comparative study with literature data

Kreuzer

Frenzel

Lampen

et al. 2019

J of Applied Toxicology

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Microarray approaches are frequently used experimental tools which have proven their value for example in the characterization of the molecular mode of action of toxicologically relevant compounds. In a regulatory context, omics techniques are still not routinely used, amongst others due to lacking standardization in experimental setup and data processing, and also due to issues with the definition of adversity. In order to exemplarily determine whether consensus transcript biomarker signatures for a certain toxicological endpoint can be derived from published microarray datasets, we here compared transcriptome data from human HepaRG hepatocarcinoma cells treated with different genotoxins, based on re‐analyzed datasets extracted from the literature. Comparison of the resulting data show that even with similarly‐acting compounds in the same cell line, considerable variation was observed with respect to the numbers and identities of differentially expressed genes. Greater concordance was observed when considering the whole data sets and biological functions associated with the genes affected. The present results highlight difficulties and possibilities in inter‐experiment comparisons of omics data and underpin the need for future efforts towards improved standardization to facilitate the use of omics data in risk assessment. Existing omics datasets may nonetheless prove valuable in establishing biological context information essential for the development of adverse outcome pathways.

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Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis

Cited by 33 publications

References 57 publications

Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety

Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety

Sensitization of Human Liver Cells Toward Fas‐Mediated Apoptosis by the Metabolically Activated Pyrrolizidine Alkaloid Lasiocarpine

Transcriptomic effect marker patterns of genotoxins – a comparative study with literature data

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