Mutagenic investigation of flavourings: Dimethyl succinate, ethyl pyruvate and aconitic acid are negative in the<i>Salmonella</i>/mammalian‐microsome test

Andersen, Pia Haubro; Jensen, N.J.

doi:10.1080/02652038409385855

Cited by 22 publications

(4 citation statements)

References 2 publications

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“…As a lipophilic agent, ethyl pyruvate can be contemplated as a therapeutic modality that can be delivered directly to the gastrointestinal tract by the oral or intrarectal route. It is likely to be safe, as ethyl pyruvate is a common additive in beverages and confectionary products, and its safety profile has been studied extensively in animals [50,51]. This study provides proof of concept to support further investigations of ethyl pyruvate as an anti-inflammatory modality in human IBD.…”

Section: Discussionmentioning

confidence: 72%

Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis

Davé

Tilstra

Matsuoka

et al. 2009

Journal of Leukocyte Biology

154

130

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Signals from stressed cells and the enteric microbiota activate macrophages and dendritic cells and mediate intestinal inflammation. HMGB1 serves as an immunogenic stimuli causing release of inflammatory cytokines by myeloid cells. Ethyl pyruvate inhibits secretion of HMGB1 and improves survival in models of endotoxemia and hemorrhagic shock. We reasoned that ethyl pyruvate may be protective in colitis, which involves similar inflammatory pathways. In IL-10(-/-) mice with established chronic colitis, ethyl pyruvate administration ameliorated colitis and reduced intestinal cytokine production. IL-10(-/-) mice demonstrated increased intestinal HMGB1 expression and decreased expression of RAGE compared with wild-type mice. Fecal HMGB1 levels were decreased in ethyl pyruvate-treated mice. Furthermore, ethyl pyruvate induced HO-1 expression in intestinal tissue. In TNBS-induced colitis, intrarectal administration of ethyl pyruvate resulted in amelioration of colitis and reduced intestinal cytokine production. In LPS-activated murine macrophages, ethyl pyruvate decreased expression of IL-12 p40 and NO production but did not affect IL-10 levels. Ethyl pyruvate did not inhibit nuclear translocation of NF-kappaB family members but attenuated NF-kappaB DNA binding. Additionally, ethyl pyruvate induced HO-1 mRNA and protein expression and HO-1 promoter activation. Moreover, ethyl pyruvate prevented nuclear-to-cytoplasmic translocation of HMGB1. In conclusion, the HMGB1/RAGE pathway has pathophysiologic and diagnostic significance in experimental colitis. Ethyl pyruvate and other strategies to inhibit HMGB1 release and function represent promising interventions in chronic inflammatory diseases.

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Section: Discussionmentioning

confidence: 72%

Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis

Davé

Tilstra

Matsuoka

et al. 2009

Journal of Leukocyte Biology

154

130

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“…Indeed, unlike other compounds, which inhibit or affect NF-κB pathway, EP has not been associated with host toxicity [43]. EP is commonly used as an additive in beverages and confectionary products, and its lack of toxicity has been demonstrated in extensive studies performed in animals [44]. Moreover, although a direct comparison of EP efficacy compared to other HMGB1 inhibitors is currently lacking, EP has been safely tested in humans and has been used in clinical trials [43].…”

Section: Discussionmentioning

confidence: 99%

HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma

et al. 2017

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Human malignant mesothelioma (MM) is an aggressive cancer linked to asbestos and erionite exposure. We previously reported that High-Mobility Group Box-1 protein (HMGB1), a prototypic damage-associated molecular pattern, drives MM development and sustains MM progression. Moreover, we demonstrated that targeting HMGB1 inhibited MM cell growth and motility in vitro, reduced tumor growth in vivo, and prolonged survival of MM-bearing mice. Ethyl pyruvate (EP), the ethyl ester of pyruvic acid, has been shown to be an effective HMGB1 inhibitor in inflammation-related diseases and several cancers. Here, we studied the effect of EP on the malignant phenotype of MM cells in tissue culture and on tumor growth in vivo using an orthotopic MM xenograft model. We found that EP impairs HMGB1 secretion by MM cells leading to reduced RAGE expression and NF-κB activation. As a consequence, EP impaired cell motility, cell proliferation, and anchorage-independent growth of MM cells. Moreover, EP reduced HMGB1 serum levels in mice and inhibited the growth of MM xenografts.Our results indicate that EP effectively hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

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“…Dimethyl succinate was not mutagenic in an Ames tests with concentrations of ≤20 000 µg/plate 168 or in a preincubation assay with concentrations of ≤10 000 μg/plate. 169…”

Section: Genotoxicitymentioning

confidence: 84%

Final Report of the Cosmetic Ingredient Review Expert Panel on the Safety Assessment of Dicarboxylic Acids, Salts, and Esters

Fiume¹,

Eldreth²,

Bergfeld³

et al. 2012

Int J Toxicol

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The CIR Expert Panel assessed the safety of dicarboxylic acids and their salts and esters as used in cosmetics. Most dicarboxylic acids function in cosmetics as pH adjusters or fragrance ingredients, but the functions of most of the salts in cosmetics are not reported. Some of the esters function as skin conditioning or fragrance ingredients, plasticizers, solvents, or emollients. The Expert Panel noted gaps in the available safety data for some of the dicarboxylic acid and their salts and esters in this safety assessment. The available data on many of the ingredients are sufficient, however, and similar structural activity relationships, biologic functions, and cosmetic product usage suggest that the available data may be extrapolated to support the safety of the entire group. The Panel concluded that the ingredients named in this report are safe in the present practices of use and concentration.

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Mutagenic investigation of flavourings: Dimethyl succinate, ethyl pyruvate and aconitic acid are negative in theSalmonella/mammalian‐microsome test

Cited by 22 publications

References 2 publications

Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis

Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis

HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma

Final Report of the Cosmetic Ingredient Review Expert Panel on the Safety Assessment of Dicarboxylic Acids, Salts, and Esters

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