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

The Reactivity of Selected Acrylate Esters toward Glutathione and Deoxyribonucleosides in Vitro:... Abstract Acrylate esters are αβ-unsaturated esters used as plastic monomers whose toxicity may involve reaction with tissue nu-cleophiles via Michael addition. Structure-activity relationships for reactivity of selected esters with glutathione (GSH) and deoxyribonucleosides were investigated in the present studies. The esters investigated were methyl acrylate, methyl methac-rylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, tetraethyleneglycol diacrylate, tetraethylenegly-col dimethacrylate, and ethyleneglycol dimethacrylate. To compare their reactivities toward GSH, esters were incubated for up to 1 hr at 3°C and pH 7.4 with either GSH or red blood cells in phosphate-buffered saline followed by measurement of free thiol. In both systems acrylate electrophilic reactivity decreased with a-methyl substitution; however, the decrease in electrophilic reactivity was more evident in the cell-free system than in the red blood cell model. Increased alcohol chain length moderately affected the apparent second-order rate constant for the spontaneous reaction of acrylate esters with GSH, but did not affect potency relative to cellular GSH depletion. The apparent second-order rate constants of bifunctional esters are more than twice the rate constants of the much smaller monofunctional esters. Ethyl acrylate, a reactive acrylate ester based upon glutathione alkylation, has been designated a class 2B (suspect human) carcinogen by the International Agency for Research on Cancer. To detect possible DNA alkylation by acrylate esters in vitro, ethyl acrylate was incubated with deoxyribonucleosides for up to 24 hr at pH 6.7 or 7.4 and 37°C or up to 8 hr and 50°C. HPLC analysis revealed no detectable adduct formation. The results suggest that reactivity of acrylate esters toward thiols is not indicative of their reactivity toward DNA. This content is only available as a PDF. Author notes 1Present address: Division of Toxicology, Department of Environmental Health Science, School of Hygiene, Johns Hopkins University, Baltimore, MD 21205. 2Present address: Bristol-Myers Squibb, P.O. Box 191, New Brunswick, NJ 08903. 3Present address: Pfizer Inc., Corporate Environment, Health and Safety, New York, NY 10017. © 1994 by the Society of Toxicology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicological Sciences Oxford University Press

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

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Publisher
Oxford University Press
Copyright
© 1994 by the Society of Toxicology
ISSN
1096-6080
eISSN
1096-0929
DOI
10.1093/toxsci/22.4.543
Publisher site
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Abstract

Abstract Acrylate esters are αβ-unsaturated esters used as plastic monomers whose toxicity may involve reaction with tissue nu-cleophiles via Michael addition. Structure-activity relationships for reactivity of selected esters with glutathione (GSH) and deoxyribonucleosides were investigated in the present studies. The esters investigated were methyl acrylate, methyl methac-rylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, tetraethyleneglycol diacrylate, tetraethylenegly-col dimethacrylate, and ethyleneglycol dimethacrylate. To compare their reactivities toward GSH, esters were incubated for up to 1 hr at 3°C and pH 7.4 with either GSH or red blood cells in phosphate-buffered saline followed by measurement of free thiol. In both systems acrylate electrophilic reactivity decreased with a-methyl substitution; however, the decrease in electrophilic reactivity was more evident in the cell-free system than in the red blood cell model. Increased alcohol chain length moderately affected the apparent second-order rate constant for the spontaneous reaction of acrylate esters with GSH, but did not affect potency relative to cellular GSH depletion. The apparent second-order rate constants of bifunctional esters are more than twice the rate constants of the much smaller monofunctional esters. Ethyl acrylate, a reactive acrylate ester based upon glutathione alkylation, has been designated a class 2B (suspect human) carcinogen by the International Agency for Research on Cancer. To detect possible DNA alkylation by acrylate esters in vitro, ethyl acrylate was incubated with deoxyribonucleosides for up to 24 hr at pH 6.7 or 7.4 and 37°C or up to 8 hr and 50°C. HPLC analysis revealed no detectable adduct formation. The results suggest that reactivity of acrylate esters toward thiols is not indicative of their reactivity toward DNA. This content is only available as a PDF. Author notes 1Present address: Division of Toxicology, Department of Environmental Health Science, School of Hygiene, Johns Hopkins University, Baltimore, MD 21205. 2Present address: Bristol-Myers Squibb, P.O. Box 191, New Brunswick, NJ 08903. 3Present address: Pfizer Inc., Corporate Environment, Health and Safety, New York, NY 10017. © 1994 by the Society of Toxicology

Journal

Toxicological Sciences – Oxford University Press

Published: May 1, 1994

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