Journal Article

Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite.

T Y Ho and G Witz

in Carcinogenesis

Volume 18, issue 4, pages 739-744
Published in print April 1997 | ISSN: 0143-3334
Published online April 1997 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/18.4.739
Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite.

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The hematotoxicity of benzene, a human leukemogen, has been postulated to be mediated by reactive metabolites and involve cell damage caused by reactive oxygen species. Because expression of the transcription factors AP-1 and NF-kappaB is sensitive to the redox state in eukaryotic cells, the DNA binding activity of AP-1 and NF-kappaB was examined in HL-60 promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a microsomal hematotoxic metabolite of benzene. There was little AP-1 binding activity in nuclear extracts from control HL-60 cells based on electrophoretic mobility shift assays. Exposure to 0.1 microM MUC for 4 h resulted in significantly increased levels of nuclear protein with high sequence specificity for the consensus AP-1 sequence. In addition, electrophoretic mobility shift assays showed a strong increase in the binding of a factor to the NF-kappaB site. The latter was highest in nuclear extracts from HL-60 cells treated with 1.0 microM muconaldehyde and cultured for 4 h. Exposure of HL-60 cells to muconaldehyde resulted in an increase in c-fos and c-jun mRNA levels. Western blot analysis showed that the protein levels of c-jun increased in HL-60 cells treated with 1 microM muconaldehyde and cultured for 4-6 h and subsequently decreased gradually. Increased AP-1 binding was observed in bone marrow cells from B6C3F1 mice 2 h after administration of 440 mg/kg benzene. We suggest that increased gene expression of NF-kappaB and AP-1 binding activity and up-regulation of c-fos and c-jun may play a role in the mechanism of benzene leukemogenesis.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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