Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells

Publication type:
Journal article
Metadata:
Autoren
  • Sara Abdelfatah
  • Janine Nass
  • Caroline Knorz
  • Sabine M Klauck
  • Jan-Heiner Kuepper
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000642027900001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s10565-021-09599-9
eISSN
1573-6822
Externe Identifier
  • Clarivate Analytics Document Solution ID: 0I5EP
  • PubMed Identifier: 33884520
ISSN
0742-2091
Ausgabe der Veröffentlichung
2
Zeitschrift
CELL BIOLOGY AND TOXICOLOGY
Schlüsselwörter
  • Herbal products
  • Food safety
  • Pyrrolizidine alkaloids
  • Systems biology
  • Transcriptomics
  • Toxicology
Paginierung
325 - 345
Datum der Veröffentlichung
2022
Status
Published
Titel
Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells
Sub types
  • Article
Ausgabe der Zeitschrift
38

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Abstract</jats:title><jats:p>Pyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations are responsible for serious hepatotoxicity and hepatocarcinogenesis. Health authorities have to set legal limit values to guarantee the safe consumption of plant-based nutritional and medical products without harmful health. Toxicological and chemical analytical methods are conventionally applied to determine legally permitted limit values for PAs. In the present investigation, we applied a highly sensitive transcriptomic approach to investigate the effect of low concentrations of five PAs (lasiocarpine, riddelliine, lycopsamine, echimidine, and monocrotaline) on human cytochrome P450 3A4-overexpressing HepG2 clone 9 hepatocytes. The transcriptomic profiling of deregulated gene expression indicated that the PAs disrupted important signaling pathways related to cell cycle regulation and DNA damage repair in the transfected hepatocytes, which may explain the carcinogenic PA effects. As PAs affected the expression of genes that involved in cell cycle regulation, we applied flow cytometric cell cycle analyses to verify the transcriptomic data. Interestingly, PA treatment led to an arrest in the S phase of the cell cycle, and this effect was more pronounced with more toxic PAs (i.e., lasiocarpine and riddelliine) than with the less toxic monocrotaline. Using immunofluorescence, high fractions of cells were detected with chromosome congression defects upon PA treatment, indicating mitotic failure. In conclusion, the tested PAs revealed threshold concentrations, above which crucial signaling pathways were deregulated resulting in cell damage and carcinogenesis. Cell cycle arrest and DNA damage repair point to the mutagenicity of PAs. The disturbance of chromosome congression is a novel mechanism of Pas, which may also contribute to PA-mediated carcinogenesis. Transcriptomic, cell cycle, and immunofluorescence analyses should supplement the standard techniques in toxicology to unravel the biological effects of PA exposure in liver cells as the primary target during metabolization of PAs.</jats:p> <jats:p><jats:bold>Graphical abstract</jats:bold></jats:p>
Autoren
  • Sara Abdelfatah
  • Janine Naß
  • Caroline Knorz
  • Sabine M Klauck
  • Jan-Heiner Küpper
  • Thomas Efferth
DOI
10.1007/s10565-021-09599-9
eISSN
1573-6822
ISSN
0742-2091
Ausgabe der Veröffentlichung
2
Zeitschrift
Cell Biology and Toxicology
Sprache
en
Online publication date
2021
Paginierung
325 - 345
Datum der Veröffentlichung
2022
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s10565-021-09599-9
Datum der Datenerfassung
2022
Titel
Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells
Ausgabe der Zeitschrift
38

Data source: Crossref

Abstract
Pyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations are responsible for serious hepatotoxicity and hepatocarcinogenesis. Health authorities have to set legal limit values to guarantee the safe consumption of plant-based nutritional and medical products without harmful health. Toxicological and chemical analytical methods are conventionally applied to determine legally permitted limit values for PAs. In the present investigation, we applied a highly sensitive transcriptomic approach to investigate the effect of low concentrations of five PAs (lasiocarpine, riddelliine, lycopsamine, echimidine, and monocrotaline) on human cytochrome P450 3A4-overexpressing HepG2 clone 9 hepatocytes. The transcriptomic profiling of deregulated gene expression indicated that the PAs disrupted important signaling pathways related to cell cycle regulation and DNA damage repair in the transfected hepatocytes, which may explain the carcinogenic PA effects. As PAs affected the expression of genes that involved in cell cycle regulation, we applied flow cytometric cell cycle analyses to verify the transcriptomic data. Interestingly, PA treatment led to an arrest in the S phase of the cell cycle, and this effect was more pronounced with more toxic PAs (i.e., lasiocarpine and riddelliine) than with the less toxic monocrotaline. Using immunofluorescence, high fractions of cells were detected with chromosome congression defects upon PA treatment, indicating mitotic failure. In conclusion, the tested PAs revealed threshold concentrations, above which crucial signaling pathways were deregulated resulting in cell damage and carcinogenesis. Cell cycle arrest and DNA damage repair point to the mutagenicity of PAs. The disturbance of chromosome congression is a novel mechanism of Pas, which may also contribute to PA-mediated carcinogenesis. Transcriptomic, cell cycle, and immunofluorescence analyses should supplement the standard techniques in toxicology to unravel the biological effects of PA exposure in liver cells as the primary target during metabolization of PAs.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Science, Johannes Gutenberg University, Mainz, Germany.
Autoren
  • Sara Abdelfatah
  • Janine Naß
  • Caroline Knorz
  • Sabine M Klauck
  • Jan-Heiner Küpper
  • Thomas Efferth
DOI
10.1007/s10565-021-09599-9
eISSN
1573-6822
Externe Identifier
  • PubMed Identifier: 33884520
  • PubMed Central ID: PMC8986750
Funding acknowledgements
  • Ministry of social affairs, Labor, Health and Demography Rhineland-Palatinate: 633-2
Open access
true
ISSN
0742-2091
Ausgabe der Veröffentlichung
2
Zeitschrift
Cell biology and toxicology
Schlüsselwörter
  • Clone Cells
  • Humans
  • DNA Damage
  • Pyrrolizidine Alkaloids
  • Monocrotaline
  • Cell Cycle
  • Hep G2 Cells
  • Transcriptome
  • Carcinogenesis
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Open access status
Open Access
Paginierung
325 - 345
Datum der Veröffentlichung
2022
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2021
Titel
Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
38

Files

https://link.springer.com/content/pdf/10.1007/s10565-021-09599-9.pdf https://europepmc.org/articles/PMC8986750?pdf=render

Data source: Europe PubMed Central

Abstract
Pyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations are responsible for serious hepatotoxicity and hepatocarcinogenesis. Health authorities have to set legal limit values to guarantee the safe consumption of plant-based nutritional and medical products without harmful health. Toxicological and chemical analytical methods are conventionally applied to determine legally permitted limit values for PAs. In the present investigation, we applied a highly sensitive transcriptomic approach to investigate the effect of low concentrations of five PAs (lasiocarpine, riddelliine, lycopsamine, echimidine, and monocrotaline) on human cytochrome P450 3A4-overexpressing HepG2 clone 9 hepatocytes. The transcriptomic profiling of deregulated gene expression indicated that the PAs disrupted important signaling pathways related to cell cycle regulation and DNA damage repair in the transfected hepatocytes, which may explain the carcinogenic PA effects. As PAs affected the expression of genes that involved in cell cycle regulation, we applied flow cytometric cell cycle analyses to verify the transcriptomic data. Interestingly, PA treatment led to an arrest in the S phase of the cell cycle, and this effect was more pronounced with more toxic PAs (i.e., lasiocarpine and riddelliine) than with the less toxic monocrotaline. Using immunofluorescence, high fractions of cells were detected with chromosome congression defects upon PA treatment, indicating mitotic failure. In conclusion, the tested PAs revealed threshold concentrations, above which crucial signaling pathways were deregulated resulting in cell damage and carcinogenesis. Cell cycle arrest and DNA damage repair point to the mutagenicity of PAs. The disturbance of chromosome congression is a novel mechanism of Pas, which may also contribute to PA-mediated carcinogenesis. Transcriptomic, cell cycle, and immunofluorescence analyses should supplement the standard techniques in toxicology to unravel the biological effects of PA exposure in liver cells as the primary target during metabolization of PAs.
Date of acceptance
2021
Autoren
  • Sara Abdelfatah
  • Janine Naß
  • Caroline Knorz
  • Sabine M Klauck
  • Jan-Heiner Küpper
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33884520
DOI
10.1007/s10565-021-09599-9
eISSN
1573-6822
Externe Identifier
  • PubMed Central ID: PMC8986750
Ausgabe der Veröffentlichung
2
Zeitschrift
Cell Biol Toxicol
Schlüsselwörter
  • Food safety
  • Herbal products
  • Pyrrolizidine alkaloids
  • Systems biology
  • Toxicology
  • Transcriptomics
  • Carcinogenesis
  • Cell Cycle
  • Clone Cells
  • DNA Damage
  • Hep G2 Cells
  • Humans
  • Monocrotaline
  • Pyrrolizidine Alkaloids
  • Transcriptome
Sprache
eng
Country
Switzerland
Paginierung
325 - 345
PII
10.1007/s10565-021-09599-9
Datum der Veröffentlichung
2022
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Titel
Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
38

Data source: PubMed

Author's licence
CC-BY
Autoren
  • Sara Abdelfatah
  • Janine Naß
  • Caroline Knorz
  • Sabine M Klauck
  • Jan-Heiner Küpper
  • Thomas Efferth
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • JGU-Publikationen
Resource version
Published version
DOI
10.1007/s10565-021-09599-9
File(s) embargoed
false
Open access
true
ISSN
1573-6822
Zeitschrift
Cell biology and toxicology
Schlüsselwörter
  • 570 Biowissenschaften
  • 570 Life sciences
  • 610 Medizin
  • 610 Medical sciences
Sprache
eng
Open access status
Open Access
Paginierung
325 - 345
Datum der Veröffentlichung
2022
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/7298
Herausgeber
Springer Science + Business Media B.V.
Datum der Datenerfassung
2022
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Zugang
Public
Titel
Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells
Ausgabe der Zeitschrift
38

Files

pyrrolizidine_alkaloids_cause-20220701131337232.pdf

Data source: OPENSCIENCE.UB

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