The Reactivity of Selected Acrylate Esters toward Glutathione and Deoxyribonucleosides <i>in Vitro</i>: Structure-Activity Relationships

MCCARTHY, TIMOTHY J.; Hayes, Eileen P.; SCHWARTZ, CHARLES S.; Witz, Gisela

doi:10.1093/toxsci/22.4.543

Cited by 21 publications

(25 citation statements)

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“…The TEGDMA monomer is an ester of an α,β‐unsaturated carboxylic acid that can react with various intracellular nucleophils at both α,β‐unsaturated β carbons (Michael addition) 16. Acrylate and methacrylate‐mediated toxicity have been correlated with their potency as Michael‐type acceptors, and the toxicity of acrylates generally is associated with their chemical reactivity towards glutathione 17. Moreover, TEGDMA caused mutation in the gene of hypoxanthine‐guanidine phosphoribosyltransferase in V 79 cells 8.…”

Section: Discussionmentioning

confidence: 99%

TEGDMA‐induced toxicity in human fibroblasts is associated with early and drastic glutathione depletion with subsequent production of oxygen reactive species

Stanislawski¹,

Lefeuvre²,

Bourd³

et al. 2003

J Biomedical Materials Res

208

139

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Triethylene glycol dimethacrylate (TEGDMA) is a dentin-bonding agent and a major component of various dental restorative biomaterials. TEGDMA monomers are released from dental resins and induce dental pulp inflammation and necrosis. In this study, we have investigated the mechanism of TEGDMA-induced cytotoxicity of fibroblasts. Treatment of cultured human gingival and pulpal fibroblasts with 0.1-3 mM of TEGDMA for 24 h induced a concentration-dependent and variable cytotoxic effect. Fifty percent of toxicity (TC(50)) was obtained with 1.2 +/- 0.9 and 2.6 +/- 1.1 mM of TEGDMA for gingival and pulpal fibroblasts, respectively. Moreover, TEGDMA-induced cytotoxicity was associated with an early and drastic depletion of cellular glutathione (GSH), which started at 15-30 min and was almost complete at 4-6 h. Antioxidants, such as Trolox (0.01 mM), ascorbate (0.2 mM), and N-acetylcysteine (NAC) (5 mM) prevented the TEGDMA-induced cytotoxicity while GSH depletion was partially inhibited. Finally, a late production of reactive oxygen species (ROS) occurred in fibroblasts treated with TEGDMA for 3-4 h, as determined by 2',7'-dichlorofluorescein fluorescence, and was completely inhibited by Trolox (5 microM). The data show that TEGDMA induced a drastic GSH depletion followed by production of ROS, which may contribute to the toxicity of gingival and pulpal fibroblasts. Antioxidants, such as NAC, ascorbate, and particularly Trolox, appear useful in preventing cell damage mediated by resin-containing dental restorative materials.

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Section: Discussionmentioning

confidence: 99%

TEGDMA‐induced toxicity in human fibroblasts is associated with early and drastic glutathione depletion with subsequent production of oxygen reactive species

Stanislawski¹,

Lefeuvre²,

Bourd³

et al. 2003

J Biomedical Materials Res

208

139

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“…Although GSH reactivity of acrylic compounds has been measured by several researchers [19,20,35], we only found one data set containing different acrylates and methacrylates. We used this data, reported by McCarthy et al [20], to test the validity of the QSPR presented above ( Table 5). Two compounds of this test set, ethyl acrylate and methyl methacrylate, were also present in the training set.…”

Section: Validation Of the Quantitative Structure-property Relationshmentioning

confidence: 99%

“…It has an important function in the phase 2 metabolism of xenobiotic compounds, where it acts as scavengerof free electrophiles and as cosubstrate of glutathione transferases. In the literature, GSH reaction rates towards different electrophiles have been reported along with a number of QSARs [16][17][18][19][20]. Michael addition, a nucleophilic addition on C ␤ (Fig.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Structure–property Relationships for the Chemical Reactivity of Acrylates and Methacrylates

Freidig¹,

Verhaar²,

Hermens³

1999

Environ Toxicol Chem

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Abstract-Reactivity towards three different nucleophiles was measured for a training set of six acrylates and seven methacrylates. The reactions studied were neutral and base-catalyzed hydrolysis and Michael addition of reduced glutathione (GSH). A linear free energy relationship (LFER) was established for the base-catalyzed hydrolysis rate constants of methacrylates, with the Taft parameter * as single descriptor. The GSH reactivity could be modeled with a partial least square regression (PLS) using four quantum chemical ground state parameters describing the difference in frontier orbital interaction and coulombic forces within the training set. Literature data for GSH reactivity was used to test the applicability of the PLS model. Differences in acute fish toxicity for structurally similar acrylates and methacrylates could be explained by their different potency as Michael-type acceptors.

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“…Scaffolds based on classical polyacrylates proved to be harmful due to residual functional groups, monomer and erosion products, which have an adverse effect on the cells already adhered to the scaffold's surface and inhibit further cell adhesion by Michael addition to amino or thiol containing groups in proteins or DNA 2, 4. Additionally, radical polymerization of acrylates forms a high molecular polymer backbone (e.g., 70,000 g mol −1 ) that cannot be transported within the human body after degradation.…”

Section: Introductionmentioning

confidence: 99%

Splenic suppressor of cytokine signaling 3 transgene expression affects T cell responses and prevents development of collagen‐induced arthritis

Veenbergen¹,

Bennink²,

Hooge³

et al. 2008

Arthritis & Rheumatism

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Objective. Members of the suppressor of cytokine signaling (SOCS) family are key negative intracellular regulators of cytokine and growth factor responses, including those that regulate immune responses in autoimmune disorders, such as rheumatoid arthritis (RA). The aim of this study was to investigate modulation of T cell immunity for the treatment of experimental arthritis, via enhanced expression of SOCS-3 in splenic antigen-presenting cells (APCs) obtained after intravenous injection of adenovirus encoding SOCS-3.Methods. DBA/1 mice were immunized with type II collagen, and adenovirus vectors were administered by intravenous injection before the clinical onset of collagen-induced arthritis (CIA). Splenic cellular responses were analyzed by measuring cytokine production, using Luminex multi-analyte technology. Th cell populations were analyzed by flow cytometry.Results. Systemic delivery of adenovirus encoding SOCS-3 resulted in enhanced transgene expression in splenic APCs, which led to decreased production of interleukin-23 (IL-23), IL-6, and tumor necrosis factor ␣, but significantly higher production of antiinflammatory IL-10, by these cells. Fluorescence-activated cell sorting analysis showed increased numbers of splenic CD4؉ T cells after SOCS-3 treatment. In the presence of SOCS-3-transduced APCs, however, purified splenic CD3؉ T cells showed reduced antigen-specific proliferation and a significant reduction in the production of interferon-␥ (؊43%), IL-4 (؊41%), and IL-17 (؊70%). Interestingly, the altered splenic cellular responses were accompanied by a protective effect on CIA development, and histologic analysis of knee joints showed reduced joint inflammation and connective tissue destruction.Conclusion. This study demonstrates effective prevention of CIA after intravenously induced overexpression of SOCS-3; this is probably caused by the generation of tolerogenic APCs, which have an inhibitory effect on Th1, Th2, and especially, Th17 cell activity.

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The Reactivity of Selected Acrylate Esters toward Glutathione and Deoxyribonucleosides in Vitro: Structure-Activity Relationships

Cited by 21 publications

References 0 publications

TEGDMA‐induced toxicity in human fibroblasts is associated with early and drastic glutathione depletion with subsequent production of oxygen reactive species

TEGDMA‐induced toxicity in human fibroblasts is associated with early and drastic glutathione depletion with subsequent production of oxygen reactive species

Quantitative Structure–property Relationships for the Chemical Reactivity of Acrylates and Methacrylates

Splenic suppressor of cytokine signaling 3 transgene expression affects T cell responses and prevents development of collagen‐induced arthritis

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