Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: implications for molecular dosimetry.
We have investigated the formation of DNA adducts in the bone marrow and white blood cells of male B6C3F1 mice treated with benzene using P1-enhanced 32P-postlabeling. No adducts were detected in the bone marrow of controls or mice treated with various doses of benzene once a day. After twice-daily treatment for 1 to 7 days with benzene, 440 mg/kg, one major (no. 1) and up to two minor DNA adducts were detected in both the bone marrow and white blood cells. The relative adduct levels in these cells ranged from 0.06 to 1.46 x 10(-7). a significant correlation (r2 = 0.95) between levels of adducts in bone marrow and white blood cells was observed. After a 7-day treatment with benzene, 440 mg/kg twice a day, the number of cells per femur decreased from 1.6 x 10(7) to 0.85 x 10(7), indicating myelotoxicity. In contrast, administration of benzene once a day produced only a small decrease in bone marrow cellularity. The observed induction of toxicity in bone marrow was paralleled by formation of DNA adducts. In vitro treatment of bone marrow with hydroquinone (HQ) for 24 hr produced the same DNA adducts as found after treatment of mice with benzene, suggesting that HQ is the principal metabolite of benzene leading to DNA adduct formation in vivo. Using P-postlabeling the principal DNA adduct formed in vivo was compared with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate. The results of this comparison demonstrated that the DNA adduct formed in vivo co-chromatographs with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate. These studies indicate that metabolic activation of benzene leads to the formation of DNA adducts in bone marrow and white blood cells and suggest that measurement of DNA adducts in white blood cells may be an indicator of biological effect following benzene exposure.
Bodell
W J
WJ
Brain Tumor Research Center, University of California, San Francisco 94143-0806, USA.
Pathak
D N
DN
Lévay
G
G
Ye
Q
Q
Pongracz
K
K
D000818:Animals; D001554:Benzene / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells; D018736:DNA Adducts / Q000096:biosynthesis* / Q000097:blood / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure
D018736:DNA Adducts; D001554:Benzene