TY - JOUR
T1 - The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems
AU - Loecken, Elisabeth M.
AU - Dasari, Surendra
AU - Hill, Salisha
AU - Tabb, David L.
AU - Guengerich, F. Peter
PY - 2009/6/15
Y1 - 2009/6/15
N2 - 1,2-Dibromoethane and 1,3-butadiene are cancer suspects present in the environment and have been used widely in industry. The mutagenic properties of 1,2-dibromoethane and the 1,3-butadiene oxidation product diepoxybutane are thought to be related to the bis-electrophilic character of these chemicals. The discovery that overexpression of O6-alkylguanine alkyltransferase (AGT) enhances bis-electrophileinduced mutagenesis prompted a search for other proteins that may act by a similar mechanism. A human liver screen for nuclear proteins that cross-link with DNA in the presence of 1,2-dibromoethane identified histones H2b and H3 as candidate proteins. Treatment of isolated histones H2b and H3 with diepoxybutane resulted in DNA-protein cross-links and produced protein adducts, and DNA-histone H2b cross-links were identified (immunochemically) in Escherichia coli cells expressing histone H2b. However, heterologous expression of histone H2b in E. coli failed to enhance bis-electrophile-induced mutagenesis. These results are similar to those found with the cross-link candidate glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [Loecken, E. M., and Guengerich, F. P. (2008) Chem. Res. Toxicol. 21, 453-458], but in contrast to GAPDH, histone H2b bound DNA with even higher affinity than AGT. The extent of DNA cross-linking of isolated histone H2b was similar to that of AGT, suggesting that differences in postcross-linking events explain the difference in mutagenesis.
AB - 1,2-Dibromoethane and 1,3-butadiene are cancer suspects present in the environment and have been used widely in industry. The mutagenic properties of 1,2-dibromoethane and the 1,3-butadiene oxidation product diepoxybutane are thought to be related to the bis-electrophilic character of these chemicals. The discovery that overexpression of O6-alkylguanine alkyltransferase (AGT) enhances bis-electrophileinduced mutagenesis prompted a search for other proteins that may act by a similar mechanism. A human liver screen for nuclear proteins that cross-link with DNA in the presence of 1,2-dibromoethane identified histones H2b and H3 as candidate proteins. Treatment of isolated histones H2b and H3 with diepoxybutane resulted in DNA-protein cross-links and produced protein adducts, and DNA-histone H2b cross-links were identified (immunochemically) in Escherichia coli cells expressing histone H2b. However, heterologous expression of histone H2b in E. coli failed to enhance bis-electrophile-induced mutagenesis. These results are similar to those found with the cross-link candidate glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [Loecken, E. M., and Guengerich, F. P. (2008) Chem. Res. Toxicol. 21, 453-458], but in contrast to GAPDH, histone H2b bound DNA with even higher affinity than AGT. The extent of DNA cross-linking of isolated histone H2b was similar to that of AGT, suggesting that differences in postcross-linking events explain the difference in mutagenesis.
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U2 - 10.1021/tx900037u
DO - 10.1021/tx900037u
M3 - Article
C2 - 19364102
AN - SCOPUS:67449113183
SN - 0893-228X
VL - 22
SP - 1069
EP - 1076
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 6
ER -