Mode of action-based risk assessment of genotoxic carcinogens

Hartwig, Andrea; Arand, Michael; Epe, Bernd; Guth, Sabine; Jahnke, Gunnar; Lampen, Alfonso; Martus, Hans-Joerg; Monien, Bernhard H.; Rietjens, Ivonne M.C.M.; Schmitz‐Spanke, Simone; Schriever‐Schwemmer, G.; Steinberg, Pablo; Eisenbrand, Gerhard

doi:10.1007/s00204-020-02733-2

Cited by 121 publications

(99 citation statements)

References 550 publications

(736 reference statements)

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“…Considering the widespread use of Nissle 1917, as a probiotic and as a platform to develop live bacterial therapeutics, ensuring its safety is of paramount importance. Genotoxic carcinogens are classically conceived to represent a risk factor with no threshold dose, because little numbers or even one DNA lesion may result in mutation and increased tumor risk (Hartwig et al, 2020). Production of mutagenic colibactin by Nissle 1917 is thus a serious health concern that must be addressed.…”

Section: Discussionmentioning

confidence: 99%

A toxic friend: Genotoxic and mutagenic activity of the probiotic strainEscherichia coliNissle 1917

Nougayrède

Chagneau

Motta

et al. 2021

Preprint

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The probiotic Escherichia coli strain Nissle 1917 (DSM 6601, Mutaflor), generally considered as beneficial and safe, has been used for a century to treat various intestinal diseases. However, Nissle 1917 hosts in its genome the pks pathogenicity island that codes for the biosynthesis of the genotoxin colibactin. Colibactin is a potent DNA alkylator, suspected to play a role in colorectal cancer development. We show in this study that Nissle 1917 is functionally capable of producing colibactin and inducing interstrand crosslinks in the genomic DNA of epithelial cells exposed to the probiotic. This toxicity was even exacerbated with lower doses of the probiotic, when the exposed cells started to divide again but exhibited aberrant anaphases and increased gene mutation frequency. DNA damage was confirmed in vivo in mouse models of intestinal colonization, demonstrating that Nissle 1917 produces the genotoxin in the gut lumen. Although it is possible that daily treatment of adult humans with their microbiota does not produce the same effects, administration of Nissle 1917 as a probiotic or as a chassis to deliver therapeutics might exert long term adverse effects and thus should be considered in a risk versus benefit evaluation. Importance: Nissle 1917 is sold as a probiotic and considered safe even though it is known since 2006 that it encodes the genes for colibactin synthesis. Colibactin is a potent genotoxin that is now linked to causative mutations found in human colorectal cancer. Many papers concerning the use of this strain in clinical applications ignore or elude this fact, or misleadingly suggest that Nissle 1917 does not induce DNA damage. Here, we demonstrate that Nissle 1917 produces colibactin in vitro and in vivo and induces mutagenic DNA damage. This is a serious safety concern that must not be ignored, for the interests of patients, the general public, health care professionals and ethical probiotic manufacturers.

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Section: Discussionmentioning

confidence: 99%

A toxic friend: Genotoxic and mutagenic activity of the probiotic strainEscherichia coliNissle 1917

Nougayrède

Chagneau

Motta

et al. 2021

Preprint

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“…Until now, more than 20 purified PAs, PA-metabolites, or plant extracts containing PAs have been demonstrated to induce tumors in rodents [9]. It should be noted that the carcinogenic activity of PAs appears to parallel their mutagenic behavior [33] but not their hepatotoxicity. Therefore, it is necessary to distinguish in the (regulatory) references exactly which of the endpoints are referenced by the measures/statements.…”

Section: Carcinogenicitymentioning

confidence: 99%

Regulatory Perspectives of Pyrrolizidine Alkaloid Contamination in Herbal Medicinal Products

Wiesner

2021

Planta Med

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The toxicity of plants containing certain pyrrolizidine alkaloids has long been recognized in grazing animals and humans. Genotoxicity and carcinogenicity data from in vitro and in vivo (animal) studies were published over the last few decades for some of the 1,2-unsaturated pyrrolizidine alkaloids, leading to regulatory action on herbal medicinal products with pyrrolizidine alkaloid-containing plants more than 30 years ago. In recent years, it has become evident that in addition to herbal medicinal products containing pyrrolizidine alkaloid-containing plants, these products may also contain pyrrolizidine alkaloids without actually including pyrrolizidine alkaloid-containing plants. This is explained by contamination by accessory herbs (weeds). The national competent authorities of the European member states and the European Medicines Agency, in this case, the Committee on Herbal Medicinal Products, reacted to these findings by setting limits for all herbal medicinal products. This review article will briefly discuss the data leading to the establishment of thresholds and the regulatory developments and consequences, as well as the current discussions and research in this area.

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“…Data on carcinogenicity of allylic phenylpropenes were summarized in a mini review by Hartwig et al (2020). Conclusively, α‐asarone and β‐asarone are the only known propenylic phenylpropenes showing similar hepatotumorigenic potential and potency in rodents compared with their allylic relatives.…”

Section: Toxicodynamicmentioning

confidence: 99%

α‐Asarone, β‐asarone, and γ‐asarone: Current status of toxicological evaluation

Uebel

Hermes

Haupenthal

et al. 2020

J of Applied Toxicology

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Asarone isomers are naturally occurring in Acorus calamus Linné, Guatteria gaumeri Greenman, and Aniba hostmanniana Nees. These secondary plant metabolites belong to the class of phenylpropenes (phenylpropanoids or alkenylbenzenes). They are further chemically classified into the propenylic trans-and cis-isomers α-asarone and β-asarone and the allylic γ-asarone.Flavoring, as well as potentially pharmacologically useful properties, enables the application of asarone isomers in fragrances, food, and traditional phytomedicine not only since their isolation in the 1950s. However, efficacy and safety in humans are still not known. Preclinical evidence has not been systematically studied, and several pharmacological effects have been reported for extracts of Acorus calamus and propenylic asarone isomers. Toxicological data are rare and not critically evaluated altogether in the 21st century yet. Therefore, within this review, available toxicological data of asarone isomers were assessed in detail. This assessment revealed that cardiotoxicity, hepatotoxicity, reproductive toxicity, and mutagenicity as well as carcinogenicity were described for propenylic asarone isomers with varying levels of reliability. The toxicodynamic profile of γ-asarone is unknown except for mutagenicity.Based on the estimated daily exposure and reported adverse effects, officials restricted or published recommendations for the use of β-asarone and preparations of Acorus calamus. In contrast, α-asarone and γ-asarone were not directly addressed due to a limited data situation.

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Mode of action-based risk assessment of genotoxic carcinogens

Cited by 121 publications

References 550 publications

A toxic friend: Genotoxic and mutagenic activity of the probiotic strainEscherichia coliNissle 1917

A toxic friend: Genotoxic and mutagenic activity of the probiotic strainEscherichia coliNissle 1917

Regulatory Perspectives of Pyrrolizidine Alkaloid Contamination in Herbal Medicinal Products

α‐Asarone, β‐asarone, and γ‐asarone: Current status of toxicological evaluation

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