Mutagenicity of stereochemical configurations of 1,2-epoxybutene and 1,2

3,4-diepoxybutane in human lymphblastoid cells

Quanxin Meng, Diana L. Redetzke, Linda C. Hackfeld, Richard P. Hodge, Dale M. Walker, Vernon E. Walker

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The carcinogenicity of 1,3-butadiene (BD) is related to its bioactivation to several DNA-reactive metabolites; accumulating evidence suggests that the stereochemistry of these BD intermediates may play a significant role in the mutagenic and carcinogenic actions of the parent compound. The objective of this study was to evaluate the cytotoxicity and mutagenicity of stereochemical forms of 1,2-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB), two genotoxic BD metabolites, in a human lymphoblastoid cell line, TK6. Cytotoxicity was measured by comparing cloning efficiencies in chemical-exposed cells versus those in control cells. The hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK) mutant frequencies (MFs) were measured using a cell cloning assay. HPRT mutants collected from cells exposed to the three forms of DEB were analyzed by PCR to characterize large genetic alterations. All the three stereoisomers of DEB caused increased HPRT and TK MFs compared to the concurrent control samples. There were no significant differences in cytotoxicity or mutagenicity among the three isomers of DEB in TK6 cells. Molecular analysis of HPRT mutants revealed similar distributions of types of mutations among the three isomers of DEB. There were also no statistically significant differences in mutagenic efficiencies between the two isomers of EB in TK6 cells. These results were consistent with the in vivo findings that there was little difference in the mutagenic efficiencies of racemic-DEB versus meso-DEB in rodents. Thus, in terms of mutagenic efficiency, stereochemical configurations of EB and DEB are not likely to play a significant role in the mutagenicity and carcinogenicity of BD.

Original languageEnglish (US)
Pages (from-to)207-218
Number of pages12
JournalChemico-Biological Interactions
Volume166
Issue number1-3
DOIs
StatePublished - Mar 20 2007

Fingerprint

Hypoxanthine Phosphoribosyltransferase
Cytotoxicity
Isomers
Thymidine Kinase
Cloning
Metabolites
Organism Cloning
Stereochemistry
Stereoisomerism
3,4-epoxy-1-butene
erythritol anhydride
Rodentia
Assays
Cells
Cell Line
Polymerase Chain Reaction
Mutation
1,3-butadiene
DNA

Keywords

  • 1,3-Butadiene
  • Epoxy metabolites
  • Mutagenicity
  • Stereoisomer

ASJC Scopus subject areas

  • Toxicology

Cite this

Mutagenicity of stereochemical configurations of 1,2-epoxybutene and 1,2 : 3,4-diepoxybutane in human lymphblastoid cells. / Meng, Quanxin; Redetzke, Diana L.; Hackfeld, Linda C.; Hodge, Richard P.; Walker, Dale M.; Walker, Vernon E.

In: Chemico-Biological Interactions, Vol. 166, No. 1-3, 20.03.2007, p. 207-218.

Research output: Contribution to journalArticle

Meng, Quanxin ; Redetzke, Diana L. ; Hackfeld, Linda C. ; Hodge, Richard P. ; Walker, Dale M. ; Walker, Vernon E. / Mutagenicity of stereochemical configurations of 1,2-epoxybutene and 1,2 : 3,4-diepoxybutane in human lymphblastoid cells. In: Chemico-Biological Interactions. 2007 ; Vol. 166, No. 1-3. pp. 207-218.
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AU - Walker, Vernon E.

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AB - The carcinogenicity of 1,3-butadiene (BD) is related to its bioactivation to several DNA-reactive metabolites; accumulating evidence suggests that the stereochemistry of these BD intermediates may play a significant role in the mutagenic and carcinogenic actions of the parent compound. The objective of this study was to evaluate the cytotoxicity and mutagenicity of stereochemical forms of 1,2-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB), two genotoxic BD metabolites, in a human lymphoblastoid cell line, TK6. Cytotoxicity was measured by comparing cloning efficiencies in chemical-exposed cells versus those in control cells. The hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK) mutant frequencies (MFs) were measured using a cell cloning assay. HPRT mutants collected from cells exposed to the three forms of DEB were analyzed by PCR to characterize large genetic alterations. All the three stereoisomers of DEB caused increased HPRT and TK MFs compared to the concurrent control samples. There were no significant differences in cytotoxicity or mutagenicity among the three isomers of DEB in TK6 cells. Molecular analysis of HPRT mutants revealed similar distributions of types of mutations among the three isomers of DEB. There were also no statistically significant differences in mutagenic efficiencies between the two isomers of EB in TK6 cells. These results were consistent with the in vivo findings that there was little difference in the mutagenic efficiencies of racemic-DEB versus meso-DEB in rodents. Thus, in terms of mutagenic efficiency, stereochemical configurations of EB and DEB are not likely to play a significant role in the mutagenicity and carcinogenicity of BD.

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