A proposed role played by benzene itself in the induction of acute cytopenia: inhibition of DNA synthesis.
A single intraperitoneal dose of benzene (880 mg/kg) in mice inhibited DNA synthesis of bone marrow cells within one hour postinjection. However, there was no inhibitory effect on the synthesis of heme and protein at that dosage. Dose-dependent inhibition of DNA synthesis by benzene was observed over the range of 440 to 1760 mg/kg, supporting the idea that cytopenia which was observed by others following multiple doses of benzene (e.g., 440 or 880 mg/kg) might be due to the inhibitory effect of benzene on DNA synthesis. In our studies, benzene concentrations above 81 micrograms/g wet bone marrow resulted in inhibition of DNA synthesis, regardless of whether it was given ip or by inhalation. The effect of benzene itself, rather than its toxic metabolites, on DNA synthesis was further seen in experiments using a bone marrow cell culture system and cell-free DNA synthetic system. Experimental results demonstrated that benzene alone was capable of inhibiting the DNA synthesis of bone marrow cells and that the reduced DNA synthesis resulted from the inhibitory effect of benzene on DNA polymerase alpha, the enzyme that catalyzes the last step of the DNA synthetic pathway. Thus, benzene itself could play a significant role in inducing myelotoxicity in the case of acute or subacute toxicity by exerting its inhibitory effect on DNA synthesis.
Lee
E W
EW
Biomedical Science Department, General Motors Research Laboratories, Warren, MI 48090-9055.
Garner
C D
CD
Johnson
J T
JT
D000280:Administration, Inhalation; D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D004247:DNA / Q000096:biosynthesis*; D005260:Female; D006418:Heme / Q000096:biosynthesis; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D019384:Nucleic Acid Synthesis Inhibitors; D014176:Protein Biosynthesis; D013936:Thymidine / Q000378:metabolism
D019384:Nucleic Acid Synthesis Inhibitors; D006418:Heme; D004247:DNA; D007930:Leucine; D001554:Benzene; D013936:Thymidine