DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde.
Increased levels of DNA-protein cross-links (DNAPC) have been observed in vitro and in vivo following treatment with a number of chemotherapeutic alkylating agents and topoisomerase II inhibitors, that is, agents that have also been associated with the development of bone marrow depression and acute myelogenous leukemia. The current studies were undertaken to examine the effect of benzene, a bone marrow toxin and human leukemogen, on DNAPC levels in mouse bone marrow cells. Using a K+/sodium dodecyl sulfate (SDS) precipitation assay for DNAPC determination, the results indicate increased DNA-protein cross-link levels in mouse bone marrow cells at 2 and 4 but not 8 h after a single ip injection of 440 mg/kg benzene. Following the administration of multiple hematotoxic benzene doses (440 or 880 mg/kg, 2x/d for 2 d), increases in DNA-protein cross-link levels were either slight or not present. These results suggest that DNAPC induced by benzene are neither cumulative nor persistent lesions. The toxicity of benzene is mediated by a number of number of ring-hydroxylated and ring-opened compounds; therefore the present studies also examined DNAPC levels in mice administered trans,trans-muconaldehyde (MUC), a ring-opened hematotoxic and genotoxic metabolite of benzene. No marked increases in DNAPC levels were observed in CD- mouse bone marrow cells 1-12 h following a single ip injection of 3 mg/kg muconaldehyde. It is possible that multiple doses of MUC are required to induce elevated DNAPC levels in bone marrow cells of mice, since multiple doses are required for MUC-induced hematotoxicity. Other reactive metabolites and/or an interaction of reactive intermediates may also be involved in DNAPC induced by benzene.
Schoenfeld
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HA
Joint Graduate Program in Toxicology, Rutgers University/UMDNJ-Robert Wood Johnson Medical School, and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, USA.
Witz
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D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D001554:Benzene / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002469:Cell Separation; D003432:Cross-Linking Reagents / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
D000447:Aldehydes; D002273:Carcinogens; D003432:Cross-Linking Reagents; D011506:Proteins; C034476:muconaldehyde; D004247:DNA; D001554:Benzene