Enhanced toxicity of the protein cross-linkers divinyl sulfone and diethyl acetylenedicarboxylate in comparison to related monofunctional electrophiles.

Abstract

Previously, we determined that diethyl acetylenedicarboxylate (DAD), a protein cross-linker, was significantly more toxic than analogous monofunctional electrophiles. We hypothesized that other protein cross-linkers enhance toxicity similarly. In agreement with this hypothesis, the bifunctional electrophile divinyl sulfone (DVSF) was 6-fold more toxic than ethyl vinyl sulfone (EVSF) in colorectal carcinoma cells and greater than 10-fold more toxic in Saccharomyces cerevisiae. DVSF and DAD caused oligomerization of yeast thioredoxin 2 (Trx2p) in vitro and promoted Trx2p cross-linking to other proteins in yeast at cytotoxic doses. Our results suggest that protein cross-linking is considerably more detrimental to cellular homeostasis than simple alkylation.

• Authors: James D West, Chelsea E Stamm, Haley A Brown, Samantha L Justice, Kevin A Morano
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 24 Issue 9 Pg. 1457-9 (Sep 19 2011) ISSN: 1520-5010 [Electronic] United States
• PMID: 21812477 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Cross-Linking Reagents
• Cytotoxins
• Proteins
• Sulfones
• divinyl sulfone
• acetylenedicarboxylic acid dimethyl ester

Topics

• Alkylation
• Alkynes (toxicity)
• Cell Line, Tumor
• Cross-Linking Reagents (toxicity)
• Cytotoxins (toxicity)
• Humans
• Proteins (chemistry)
• Saccharomyces cerevisiae (cytology)
• Sulfones (toxicity)