Bodell W J, Pathak D N, Lévay G, Ye Q, Pongracz K
Brain Tumor Research Center, University of California, San Francisco 94143-0806, USA.
Environ Health Perspect. 1996 Dec;104 Suppl 6(Suppl 6):1189-93. doi: 10.1289/ehp.961041189.
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.
我们使用P1增强的32P后标记法，研究了用苯处理的雄性B6C3F1小鼠骨髓和白细胞中DNA加合物的形成情况。对照组或每天用不同剂量苯处理的小鼠骨髓中均未检测到加合物。在用440mg/kg苯每天处理两次，持续1至7天后，在骨髓和白细胞中均检测到一种主要的（第1号）和多达两种次要的DNA加合物。这些细胞中的相对加合物水平在0.06至1.46×10(-7)之间。观察到骨髓和白细胞中的加合物水平之间存在显著相关性（r2 = 0.95）。在用440mg/kg苯每天处理两次，持续7天后，每根股骨中的细胞数量从1.6×10(7)减少到0.85×10(7)，表明存在骨髓毒性。相比之下，每天一次给予苯只会使骨髓细胞数量略有减少。观察到的骨髓毒性诱导与DNA加合物的形成同时出现。用对苯二酚（HQ）体外处理骨髓24小时产生的DNA加合物与用苯处理小鼠后发现的相同，这表明HQ是苯在体内导致DNA加合物形成的主要代谢产物。使用P后标记法，将体内形成的主要DNA加合物与N2-(4-羟基苯基)-2'-脱氧鸟苷-3'-磷酸进行了比较。该比较结果表明，体内形成的DNA加合物与N2-(4-羟基苯基)-2'-脱氧鸟苷-3'-磷酸共色谱。这些研究表明，苯的代谢活化导致骨髓和白细胞中DNA加合物的形成，并表明测量白细胞中的DNA加合物可能是苯暴露后生物效应的一个指标。
