Abstract
Previous studies from our laboratory have demonstrated the formation of DNA–protein cross-links (DNAPC), a potentially cytotoxic and genotoxic lesion induced by many leukemogenic agents, in bone marrow cells of mice administered benzene, however, reactive benzene metabolites involved in DNAPC formation by benzene have not been characterized. The present studies examined DNA PC formation in HL60 cells treated with trans, trans-muconaldehyde (MUC), a hematotoxic ring-opened metabolite of benzene, as well as with MUC metabolites and structurally related compounds. Using a K +/SDS precipitation assay for DNAPC determination, concentration- and time-dependent increases in DNAPC formation were observed 2 and 4 h after treatment of HL60 cells with 50, 75 and 100 μM MUC. No increases in DNAPC levels were measured in HL60 cells 4 h after treatment with the MUC metabolites 6-hydroxy- trans, trans-2,4-hexadienal (HOMCHO), 6-oxo- trans, trans-2,4-hexadienoic acid (CHOMCOOH), or trans, trans-muconic acid (HOOCMCOOH), each at 100 μM. Significant increases in DNAPC levels were observed 4 h after treatment with 500 and 1000 μM HOMCHO, but not CHOMCOOH. No effect on DNAPC levels was observed 4 h after treatment with 100 μM for trans, trans-2,4-hexadienal, trans-2-hexenal, hexanal, trans, trans-2,4-hexadiene, glutaraldehyde, or acrolein. DNAPC induced by MUC and HOMCHO may be cytotoxic lesions, as increases in DNAPC levels by these compounds correlated with decreases in cell viability. Except for acrolein, compounds not inducing DNAPC at 100 μM also did not affect cell viability. These studies suggest that both aldehydic carbons of MUC contribute to DNAPC induction, and that the presence of α,β-unsaturated double bonds conjugated with the aldehyde groups increases the ability of MUC to induce DNAPC relative to the saturated dialdehyde glutaraldehyde.
Published Version
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