Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay

Jochem Louisse; Deborah Rijkers; Geert Stoopen; Wendy Jansen Holleboom; Mona Delagrange; Elise Molthof; Patrick P.J. Mulder; Ron L.A.P. Hoogenboom; Marc Audebert; Ad A.C.M. Peijnenburg

doi:10.1016/j.fct.2019.05.040

Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay

Jochem Louisse^*, Deborah Rijkers, Geert Stoopen, Wendy Jansen Holleboom, Mona Delagrange, Elise Molthof, Patrick P.J. Mulder, Ron L.A.P. Hoogenboom, Marc Audebert, Ad A.C.M. Peijnenburg

^*Corresponding author for this work

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Abstract

Pyrrolizidine alkaloids (PAs) are secondary metabolites from plants that have been found in substantial amounts in herbal supplements, infusions and teas. Several PAs cause cancer in animal bioassays, mediated via a genotoxic mode of action, but for the majority of the PAs, carcinogenicity data are lacking. It is assumed in the risk assessment that all PAs have the same potency as riddelliine, which is considered to be one of the most potent carcinogenic PAs in rats. This may overestimate the risks, since many PAs are expected to have lower potencies. In this study we determined the concentration-dependent genotoxicity of 37 PAs representing different chemical classes using the γH2AX in cell western assay in HepaRG human liver cells. Based on these in vitro data, PAs were grouped into different potency classes. The group with the highest potency consists particularly of open diester PAs and cyclic diester PAs (including riddelliine). The group of the least potent or non-active PAs includes the monoester PAs, non-esterified necine bases, PA N-oxides, and the unsaturated PA trachelanthamine. This study reveals differences in in vitro genotoxic potencies of PAs, supporting that the assumption that all PAs have a similar potency as riddelliine is rather conservative.

Original language	English
Article number	110532
Journal	Food and Chemical Toxicology
Volume	131
DOIs	https://doi.org/10.1016/j.fct.2019.05.040
Publication status	Published - 1 Sept 2019

Keywords

Genotoxicity
HepaRG
Pyrrolizidine alkaloids (PAs)
Relative potency factor (RPF)
γH2AX assay

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.fct.2019.05.040Licence: CC BY-NC-ND

Toxicologische karakterisering van nieuwe VV-issues m.b.v. proefdier vervangende methoden (WOT-02-001-066, WOT-02-002-003, WOT-02-002-017)
Beekmann, K. (Project Leader)
1/01/08 → 31/12/25
Project: LVVN project

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Louisse, J., Rijkers, D., Stoopen, G., Holleboom, W. J., Delagrange, M., Molthof, E., Mulder, P. P. J., Hoogenboom, R. L. A. P., Audebert, M., & Peijnenburg, A. A. C. M. (2019). Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay. Food and Chemical Toxicology, 131, Article 110532. https://doi.org/10.1016/j.fct.2019.05.040

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title = "Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay",

abstract = "Pyrrolizidine alkaloids (PAs) are secondary metabolites from plants that have been found in substantial amounts in herbal supplements, infusions and teas. Several PAs cause cancer in animal bioassays, mediated via a genotoxic mode of action, but for the majority of the PAs, carcinogenicity data are lacking. It is assumed in the risk assessment that all PAs have the same potency as riddelliine, which is considered to be one of the most potent carcinogenic PAs in rats. This may overestimate the risks, since many PAs are expected to have lower potencies. In this study we determined the concentration-dependent genotoxicity of 37 PAs representing different chemical classes using the γH2AX in cell western assay in HepaRG human liver cells. Based on these in vitro data, PAs were grouped into different potency classes. The group with the highest potency consists particularly of open diester PAs and cyclic diester PAs (including riddelliine). The group of the least potent or non-active PAs includes the monoester PAs, non-esterified necine bases, PA N-oxides, and the unsaturated PA trachelanthamine. This study reveals differences in in vitro genotoxic potencies of PAs, supporting that the assumption that all PAs have a similar potency as riddelliine is rather conservative.",

keywords = "Genotoxicity, HepaRG, Pyrrolizidine alkaloids (PAs), Relative potency factor (RPF), γH2AX assay",

author = "Jochem Louisse and Deborah Rijkers and Geert Stoopen and Holleboom, {Wendy Jansen} and Mona Delagrange and Elise Molthof and Mulder, {Patrick P.J.} and Hoogenboom, {Ron L.A.P.} and Marc Audebert and Peijnenburg, {Ad A.C.M.}",

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AU - Rijkers, Deborah

AU - Stoopen, Geert

AU - Holleboom, Wendy Jansen

AU - Delagrange, Mona

AU - Molthof, Elise

AU - Mulder, Patrick P.J.

AU - Hoogenboom, Ron L.A.P.

AU - Audebert, Marc

AU - Peijnenburg, Ad A.C.M.

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N2 - Pyrrolizidine alkaloids (PAs) are secondary metabolites from plants that have been found in substantial amounts in herbal supplements, infusions and teas. Several PAs cause cancer in animal bioassays, mediated via a genotoxic mode of action, but for the majority of the PAs, carcinogenicity data are lacking. It is assumed in the risk assessment that all PAs have the same potency as riddelliine, which is considered to be one of the most potent carcinogenic PAs in rats. This may overestimate the risks, since many PAs are expected to have lower potencies. In this study we determined the concentration-dependent genotoxicity of 37 PAs representing different chemical classes using the γH2AX in cell western assay in HepaRG human liver cells. Based on these in vitro data, PAs were grouped into different potency classes. The group with the highest potency consists particularly of open diester PAs and cyclic diester PAs (including riddelliine). The group of the least potent or non-active PAs includes the monoester PAs, non-esterified necine bases, PA N-oxides, and the unsaturated PA trachelanthamine. This study reveals differences in in vitro genotoxic potencies of PAs, supporting that the assumption that all PAs have a similar potency as riddelliine is rather conservative.

AB - Pyrrolizidine alkaloids (PAs) are secondary metabolites from plants that have been found in substantial amounts in herbal supplements, infusions and teas. Several PAs cause cancer in animal bioassays, mediated via a genotoxic mode of action, but for the majority of the PAs, carcinogenicity data are lacking. It is assumed in the risk assessment that all PAs have the same potency as riddelliine, which is considered to be one of the most potent carcinogenic PAs in rats. This may overestimate the risks, since many PAs are expected to have lower potencies. In this study we determined the concentration-dependent genotoxicity of 37 PAs representing different chemical classes using the γH2AX in cell western assay in HepaRG human liver cells. Based on these in vitro data, PAs were grouped into different potency classes. The group with the highest potency consists particularly of open diester PAs and cyclic diester PAs (including riddelliine). The group of the least potent or non-active PAs includes the monoester PAs, non-esterified necine bases, PA N-oxides, and the unsaturated PA trachelanthamine. This study reveals differences in in vitro genotoxic potencies of PAs, supporting that the assumption that all PAs have a similar potency as riddelliine is rather conservative.

KW - Genotoxicity

KW - HepaRG

KW - Pyrrolizidine alkaloids (PAs)

KW - Relative potency factor (RPF)

KW - γH2AX assay

U2 - 10.1016/j.fct.2019.05.040

DO - 10.1016/j.fct.2019.05.040

M3 - Article

AN - SCOPUS:85066956900

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VL - 131

JO - Food and Chemical Toxicology

JF - Food and Chemical Toxicology

M1 - 110532

ER -

Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay

Abstract

Keywords

UN SDGs

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Toxicologische karakterisering van nieuwe VV-issues m.b.v. proefdier vervangende methoden (WOT-02-001-066, WOT-02-002-003, WOT-02-002-017)

Cite this