苯并[a]芘在人乳腺组织中形成聚集性 DNA 损伤中的作用。
Role of benzo[alpha]pyrene in generation of clustered DNA damage in human breast tissue.
机构信息
Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
出版信息
Free Radic Biol Med. 2010 Jul 1;49(1):77-87. doi: 10.1016/j.freeradbiomed.2010.03.018. Epub 2010 Mar 25.
Complex DNA damage may manifest in double-strand breaks (DSBs) and non-DSB, bistranded, oxidatively induced clustered DNA lesions (OCDLs). Although the carcinogen benzo[alpha]pyrene (B[alpha]P) has been shown to induce chromosomal aberrations and transformation of mammary cells, it is not known whether this compound engenders clustered DNA damage. Normal primary breast tissue-derived cells were treated with B[alpha]P, and the levels of DNA lesions, chromosomal aberrations, total antioxidant capacity (TAC), and reactive oxygen species (ROS) were determined. DNA from cells treated with 2 and 8 microM B[alpha]P exhibited increases of 3- and 4-fold in APE1 (p<0.001), 11- and 19-fold in Endo III (p<0.001), and 8- and 15-fold in hOGG1 (p<0.001) OCDLs, respectively, compared to the 0 microM B[alpha]P-treated (control) group. Mammary cells treated with 8 microM B[alpha]P produced 0.12 aberrations per cell (p<0.05) and there was a strong positive correlation (r=0.91) between the levels of OCDLs and those of chromosomal aberrations. Finally, TAC was decreased by 25% (p<0.02), whereas ROS production increased by 2-fold (p<0.02) in cells treated with 8 microM B[alpha]P compared to the control group. In conclusion, oxidatively induced clustered DNA damage mediated through differential expression of APE1, reduced TAC, and increased ROS may play a significant role in the chemically induced transformation of normal primary mammary cells.
可能表现为双链断裂（DSB）和非双链、双股、氧化诱导的簇状 DNA 损伤（OCDL）的复杂 DNA 损伤。尽管致癌剂苯并[a]芘（B[a]P）已被证明会诱导染色体畸变和乳腺细胞转化，但尚不清楚该化合物是否会产生簇状 DNA 损伤。用 B[a]P 处理正常原代乳腺组织衍生细胞，并测定 DNA 损伤、染色体畸变、总抗氧化能力（TAC）和活性氧（ROS）的水平。用 2 和 8 μM B[a]P 处理的细胞的 DNA 中，APE1 的增加分别为 3 倍和 4 倍（p<0.001），Endo III 的增加分别为 11 倍和 19 倍（p<0.001），hOGG1 的增加分别为 8 倍和 15 倍（p<0.001）与 0 μM B[a]P 处理的（对照）组相比。用 8 μM B[a]P 处理的乳腺细胞产生 0.12 个畸变/细胞（p<0.05），并且 OCDL 水平与染色体畸变水平之间存在强正相关（r=0.91）。最后，与对照组相比，用 8 μM B[a]P 处理的细胞的 TAC 降低了 25%（p<0.02），而 ROS 产生增加了 2 倍（p<0.02）。总之，通过 APE1 的差异表达、TAC 的降低和 ROS 的增加介导的氧化诱导的簇状 DNA 损伤可能在正常原代乳腺细胞的化学诱导转化中起重要作用。
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