Pathak D N, Lévay G, Bodell W J
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143-0806, USA.
Carcinogenesis. 1995 Aug;16(8):1803-8. doi: 10.1093/carcin/16.8.1803.
We used P1-enhanced 32P-postlabeling to investigate DNA adduct formation in the bone marrow of B6C3F1 mice treated intraperitoneally with benzene (BZ). No adducts were detected in the bone marrow of controls or mice treated with various doses of BZ once a day. After twice-daily treatment with BZ, 440 mg/kg, for 1 to 7 days, one major and two minor DNA adducts were detected. The relative adduct levels ranged from 0.06-1.46 x 10(-7). In vitro treatment of bone marrow from B6C3F1 mice with various doses of hydroquinone (HQ) for 24 h also produced three DNA adducts. These adducts were the same as those formed after in vivo treatment of bone marrow with BZ. Co-chromatography experiments indicated that the principal DNA adduct detected in the bone marrow of B6C3F1 mice was the same as that detected in HL-60 cells treated with HQ. This finding suggests that HQ may be the principal metabolite of BZ leading to DNA adduct formation in vivo. DNA adduct 2 corresponds to the DNA adduct formed in HL-60 cells treated with 1,2,4-benzenetriol. DNA adduct 3 remains unidentified. After a 7-day treatment with BZ, 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 BZ once a day produced only a small decrease in bone marrow cellularity. These studies demonstrate that metabolic activation of BZ leads to the formation of DNA adducts in the bone marrow. Further investigation is required to determine the role of DNA adducts and other forms of DNA damage in the myelotoxic effects of exposure to BZ.
我们使用P1增强的32P后标记法来研究经腹腔注射苯（BZ）处理的B6C3F1小鼠骨髓中DNA加合物的形成情况。在对照组或每天接受不同剂量BZ处理的小鼠骨髓中未检测到加合物。在用440 mg/kg BZ每日处理两次，持续1至7天之后，检测到一种主要的和两种次要的DNA加合物。相对加合物水平范围为0.06 - 1.46×10(-7)。用不同剂量对苯二酚（HQ）对B6C3F1小鼠骨髓进行24小时的体外处理也产生了三种DNA加合物。这些加合物与用BZ对骨髓进行体内处理后形成的加合物相同。共色谱实验表明，在B6C3F1小鼠骨髓中检测到的主要DNA加合物与在用HQ处理的HL-60细胞中检测到的相同。这一发现表明，HQ可能是BZ在体内导致DNA加合物形成的主要代谢产物。DNA加合物2与在用1,2,4-苯三酚处理的HL-60细胞中形成的DNA加合物相对应。DNA加合物3仍未明确。在用440 mg/kg BZ每日处理两次，持续7天之后，每根股骨中的细胞数量从1.6×10(7)降至0.85×10(7)，表明存在骨髓毒性。相比之下，每天给予一次BZ仅使骨髓细胞数量略有减少。这些研究表明，BZ的代谢活化导致骨髓中DNA加合物的形成。需要进一步研究以确定DNA加合物和其他形式的DNA损伤在接触BZ的骨髓毒性作用中的作用。
