Benzene metabolite, 1,2,4-benzenetriol, induces micronuclei and oxidative DNA damage in human lymphocytes and HL60 cells.
The triphenolic metabolite of benzene, 1,2,4-benzenetriol (BT), is readily oxidized to its corresponding quinone via a semiquinone radical. During this process, active oxygen species are formed that may damage DNA and other cellular macromolecules. The ability of BT to induce micronuclei (MN) and oxidative DNA damage has been investigated in both human lymphocytes and HL60 cells. An antikinetochore antibody based micronucleus assay was used to distinguish MN containing kinetochores and potentially entire chromosomes (kinetochore-positive, K+) from those containing acentric chromosome fragments (kinetochore-negative, K-). BT increased the frequency of MN formation twofold in lymphocytes and eightfold in HL60 cells with the MN being 62% and 82% K+, respectively. A linear dose-related increase in total MN, mainly in K(+)-MN, was observed in both HL60 cells and lymphocytes. Addition of copper ions (Cu2+) potentiated the effect of BT on MN induction threefold in HL60 cells and altered the pattern of MN formation from predominantly K+ to K-. BT also increased the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a marker of active oxygen-induced DNA damage. Cu2+ again enhanced this effect. Thus, BT has the potential to cause both numerical and structural chromosomal changes in human cells. Further, it may cause point mutations indirectly by generating oxygen radicals. BT may therefore play an important role in benzene-induced leukemia.
Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley 94720.
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L
Zhang
M L
ML
Robertson
P
P
Kolachana
A J
AJ
Davison
M T
MT
Smith
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000704:Analysis of Variance; D000782:Aneuploidy; D002471:Cell Transformation, Neoplastic; D002503:Centromere / Q000187:drug effects; D003300:Copper / Q000633:toxicity; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D004357:Drug Synergism; D005260:Female; D005609:Free Radicals; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D007951:Leukemia, Myeloid; D008214:Lymphocytes / Q000187:drug effects; D015162:Micronucleus Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity*; D012044:Regression Analysis; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D005609:Free Radicals; D006873:Hydroquinones; D009153:Mutagens; D017382:Reactive Oxygen Species; C013038:hydroxyhydroquinone; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine