Urban dust particulate matter alters PAH-induced carcinogenesis by inhibition of CYP1A1 and CYP1B1
Urban dust particulate matter alters PAH-induced carcinogenesis by inhibition of CYP1A1 and CYP1B1
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DOI：
10.1093/toxsci/kfl137
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发表时间：
2007-01-01
影响因子：
3.8
通讯作者：
Baird, William M.
中科院分区：
文献类型：
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作者：
Courter, Lauren A.;Musatia-Jeknic, Tamara;Baird, William M.
多环芳烃苯并[a]芘（B[a]P）和二苯并[a，l]芘（DB[a，l]P）是研究较多的环境致癌物，但它们在复杂混合物中的致癌效力尚不确定。我们研究了城市灰尘颗粒物（UDPM）对B[a]P和DB[a，l]P的生物活化和肿瘤启动的影响。用UDPM或与B[a]P或DB[a，l]P组合局部处理SENCAR小鼠，随后每周施用促进剂12-O-十四酰基佛波醇-13乙酸酯。UDPM表现出较弱的肿瘤起始活性，但显著延迟了B[a] P诱导的肿瘤起始的两倍。当与UDPM共处理时，DB[a，l] P处理的动物与单独DB[a，l]P相比在肿瘤引发活性方面没有显着差异。肿瘤的发生与PAH-DNA加合物相关，通过P-33-postlabeling和反相高效液相色谱法检测。在UDPM处理或与B[a]P或DB[a，l]P共处理后，也检测到细胞色素P450（CYP）1A 1和1B 1蛋白的诱导，表明PAH生物活化。彗星试验进一步的遗传毒性分析表明，与PAH单独处理相比，UDPM + B[a]P或DB[a，l]P联合处理导致DNA链断裂增加。通过7-乙氧基试卤灵O-脱乙基（EROD）试验测定的CYP 1A 1和CYP 1B 1代谢活性显示，UDPM以剂量依赖性方式非竞争性抑制CYP 1A 1和CYP 1B 1 EROD活性。总体而言，这些数据表明，复杂混合物中的成分可以通过抑制PAH生物活化来改变PAH诱导的致癌作用，并影响其他遗传毒性效应，如氧化性DNA损伤。这些数据进一步表明，在预测人类癌症风险时，除了强效PAH的水平外，还必须考虑其他混合物成分的影响。
The polycyclic aromatic hydrocarbons (PAHs) benzo[a]pyrene (B[a]P) and dibenzo[a,l]pyrene (DB[a,l]P) are well-studied environmental carcinogens, however, their potency within a complex mixture is uncertain. We investigated the influence of urban dust particulate matter (UDPM) on the bioactivation and tumor initiation of B[a]P and DB[a,l]P in an initiation-promotion tumorigenesis model. SENCAR mice were treated topically with UDPM or in combination with B[a]P or DB[a,l]P, followed by weekly application of the promoter 12-O-tetradecanoylphorbol-13 acetate. UDPM exhibited weak tumor-initiating activity but significantly delayed the onset of B[a]P-induced tumor initiation by two-fold. When cotreated with UDPM, DB[a,l]P-treated animals displayed no significant difference in tumor-initiating activity, compared with DB[a,l]P alone. Tumor initiation correlated with PAH-DNA adducts, as detected by P-33-postlabeling and reversed-phase high-performance liquid chromatography. Induction of cytochrome P450 (CYP)1A1 and 1B1 proteins was also detected following UDPM treatment or cotreatment with B[a]P or DB[a,l]P, indicating PAH bioactivation. Further genotoxicity analyses by the comet assay revealed that cotreatment of UDPM plus B[a]P or DB[a,l]P resulted in increased DNA strand breaks, compared with PAH treatment alone. The metabolizing activities of CYP1A1 and CYP1B1, as measured by the 7-ethoxyresorufin O-deethylation (EROD) assay, revealed that UDPM noncompetitively inhibited CYP1A1 and CYP1B1 EROD activity in a dose-dependent manner. Overall, these data suggest that components within complex mixtures can alter PAH-induced carcinogenesis by inhibiting CYP bioactivation and influence other genotoxic effects, such as oxidative DNA damage. These data further suggest that in addition to the levels of potent PAH, the effects of other mixture components must be considered when predicting human cancer risk.