Effects of benzene metabolite treatment on granulocytic differentiation and DNA adduct formation in HL-60 cells.
Reactive metabolites of benzene (BZ) play important roles in BZ-induced hematotoxicity. Although reactive metabolites of BZ covalently bind to DNA, the significance of DNA adduct formation in the mechanism of BZ toxicity is not clear. These studies investigated the covalent binding of the BZ metabolites hydroquinone(HQ) and 1,2,4-benzenetriol(BT) using the DNA [32P]postlabeling method and explored the potential relationship between DNA adduct formation and cell differentiation in human promyelocytic leukemia (HL-60) cells, a model system for studying hematopoiesis. Maturation of HL-60 cells to granulocytes, as assessed by light and electron microscopy, was significantly inhibited in cells that were pretreated with HQ or BT prior to inducing differentiation with retinoic acid (RA). The capacity of RA-induced cells to phagocytose sheep red blood cells (RBC) and to reduce nitroblue tetrazolium (NBT), two functional parameters characteristic of mature, differentiated neutrophils, was also inhibited in cells pretreated with HQ or BT. These BZ metabolite treatments induced DNA adduct formation in HQ- but not in BT-treated cells. These results indicate that whereas HQ and BT each block granulocytic differentiation in HL-60 cells, DNA adducts were observed only following HQ treatment. Thus DNA adduct formation may be important in HQ but not in BT toxicity.
Hedli
C C
CC
Joint Graduate Program in Toxicology, Rutgers University/UMDNJ-RWJMS, Piscataway, NJ, USA.
Rao
N R
NR
Reuhl
K R
KR
Witmer
C M
CM
Snyder
R
R
D001555:Benzene Derivatives / Q000378:metabolism* / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects*; D006098:Granulocytes / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D018922:HL-60 Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology*; D009153:Mutagens / Q000494:pharmacology; D010761:Phosphorus Radioisotopes; D014212:Tretinoin / Q000494:pharmacology
D001555:Benzene Derivatives; D018736:DNA Adducts; D006873:Hydroquinones; D009153:Mutagens; D010761:Phosphorus Radioisotopes; C013038:hydroxyhydroquinone; D014212:Tretinoin; D004247:DNA; C031927:hydroquinone