Marston C P, Pereira C, Ferguson J, Fischer K, Hedstrom O, Dashwood W M, Baird W M
Department of Environmental and Molecular Toxicology, Department of Statistics and College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
Carcinogenesis. 2001 Jul;22(7):1077-86. doi: 10.1093/carcin/22.7.1077.
Human exposure to polycyclic aromatic hydrocarbons (PAH) occurs through complex mixtures such as coal tar. The effect of complex PAH mixtures on the activation of carcinogenic PAH to DNA-binding derivatives and carcinogenesis were investigated in mice treated topically with NIST (National Institute of Standards and Technology) Standard Reference Material 1597 (SRM), a complex mixture of PAH extracted from coal tar, and either additional benzo[a]pyrene (B[a]P) or dibenzo[a,l]pyrene (DB[a,l]P). In an initiation-promotion study using 12-O-tetradecanoylphorbol-13-acetate as the promoter for 25 weeks, the SRM and B[a]P co-treated mice had a similar incidence of papillomas per mouse compared with the group exposed to B[a]P alone as the initiator. PAH-DNA adduct analysis of epidermal DNA by 33P-post-labeling and reversed-phase high-performance liquid chromatography found the SRM co-treatment led to a significant decrease in the total level of DNA adducts and B[a]P-DNA adducts to less than that observed in mice treated with B[a]P alone at 6, 12 and 72 h exposure. After 24 and 48 h exposure, there was no significant difference in the levels of adducts between these groups. In the DB[a,l]P initiation-promotion study, the co-treated group had significantly fewer papillomas per mouse than mice treated with DB[a,l]P alone as initiator. Averaging over the times of exposure gave strong evidence that mice co-treated with SRM and DB[a,l]P had a significantly lower level of PAH-DNA adducts than mice treated with DB[a,l]P alone. Western immunoblots showed that both cytochrome P450 (CYP) 1A1 and 1B1 were induced by the SRM. These results are consistent with the hypothesis that two major factors determining the carcinogenic activity of PAH within a complex mixture are (i) the persistence of certain PAH-DNA adducts as well as total adduct levels, and (ii) the ability of the components present in the mixture to inhibit the activation of carcinogenic PAH by the induced CYP enzymes.
人类通过煤焦油等复杂混合物接触多环芳烃（PAH）。在局部涂抹美国国家标准与技术研究院（NIST）标准参考物质1597（SRM）（一种从煤焦油中提取的PAH复杂混合物）以及额外的苯并[a]芘（B[a]P）或二苯并[a,l]芘（DB[a,l]P）的小鼠中，研究了复杂PAH混合物对致癌性PAH激活为DNA结合衍生物及致癌作用的影响。在一项使用12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯作为启动剂进行25周的启动 - 促进研究中，与单独以B[a]P作为启动剂的组相比，SRM与B[a]P共同处理的小鼠每只小鼠的乳头状瘤发生率相似。通过33P后标记和反相高效液相色谱法对表皮DNA进行PAH - DNA加合物分析发现，SRM共同处理导致DNA加合物和B[a]P - DNA加合物的总水平在暴露6、12和72小时时显著降低，低于单独用B[a]P处理的小鼠。在暴露24和48小时后，这些组之间的加合物水平没有显著差异。在DB[a,l]P启动 - 促进研究中，共同处理组每只小鼠的乳头状瘤明显少于单独以DB[a,l]P作为启动剂处理的小鼠。对暴露时间进行平均得出有力证据，表明SRM与DB[a,l]P共同处理的小鼠的PAH - DNA加合物水平明显低于单独用DB[a,l]P处理的小鼠。蛋白质免疫印迹显示细胞色素P450（CYP）1A1和1B1均被SRM诱导。这些结果与以下假设一致，即在复杂混合物中决定PAH致癌活性的两个主要因素是：（i）某些PAH - DNA加合物的持久性以及总加合物水平，（ii）混合物中存在的成分抑制诱导的CYP酶激活致癌性PAH的能力。
