Tissue Distribution, Excretion and Pharmacokinetics of the Environmental Pollutant Dibenzo[def,p]chrysene in Mice.
Tissue Distribution, Excretion and Pharmacokinetics of the Environmental Pollutant Dibenzo[def,p]chrysene in Mice.
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DOI：
10.1021/acs.chemrestox.5b00097
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发表时间：
2015-07-20
影响因子：
4.1
通讯作者：
Chen KM
中科院分区：
文献类型：
--
作者：
Sun YW;El-Bayoumy K;Aliaga C;Awad AS;Gowda K;Amin S;Chen KM
二苯并[def，p]chrysene(DBP)是一类具有代表性的多环芳烃(PAH)，在啮齿动物体内可诱发卵巢、肺、乳腺和口腔等多个器官部位的肿瘤。这项研究的目的是验证一种假设，即DBP及其代谢物的水平达到并在靶器官中保持较长时间的水平，以及这些器官将这种致癌物代谢成可破坏DNA的活性代谢物的能力可能是其组织选择性致瘤性的原因。因此，我们使用放射性标记的[~3H]DBP来准确地评估这种致癌物的组织分布、排泄和药代动力学。我们还比较了口服DBP的小鼠在选定的靶器官(卵巢)和非靶器官(肾脏和肝脏)中DBPDE-DNA加合物的水平。结果表明，1周后，91.40±7.23%的放射性从粪便中恢复，1周后尿液中相应的放射性排泄量小于2%。24 h后，胃的放射性水平最高，其次是肠和肝脏；1周后，卵巢和肝脏等组织中的放射性水平最低；DBP的药动学分析采用一室开放模型。卵巢中(−)-抗反式DBPDE-da的水平(8.91±0.08adducts/107da)显著高于肾脏(0.69±0.09adducts/107da)和肝脏(0.63±0.11adducts/107da)的水平。总的来说，组织分布和药代动力学分析的结果可能并不完全支持我们的假设，但靶器官与非靶器官将DBP代谢成可破坏DNA的活性中间体的能力可能是其组织选择性致瘤性的原因。
Dibenzo[def,p]chrysene (DBP), a representative example of the class of polycyclic aromatic hydrocarbon (PAH), is known to induce tumors in multiple organ sites including the ovary, lung, mammary glands, and oral cavity in rodents. The goal of this study was to test the hypothesis that the levels of DBP and its metabolites that reach and retain the levels for an extended time in the target organs as well as the capacity of these organs to metabolize this carcinogen to active metabolites that can damage DNA may account for its tissue selective tumorigenicity. Therefore, we used the radiolabeled [3H] DBP to accurately assess the tissue distribution, excretion, and pharmacokinetics of this carcinogen. We also compared the levels of DBPDE-DNA adducts in a select target organ (ovary) and nontarget organs (kidney and liver) in mice treated orally with DBP. Our results showed that after 1 week, 91.40 ± 7.23% of the radioactivity was recovered in the feces; the corresponding value excreted in the urine was less than 2% after 1 week. After 24 h, the stomach had the highest radioactivity followed by the intestine and the liver; however, after 1 week, levels of the radioactivity in these organs were the lowest among tissues examined including the ovary and liver; the pharmacokinetic analysis of DBP was conducted using a one compartment open model. The level of (−)-anti-trans-DBPDE-dA in the ovaries (8.91 ± 0.08 adducts/107 dA) was significantly higher (p < 0.01) than the levels of adducts in kidneys (0.69 ± 0.09 adducts/107 dA) and livers (0.63 ± 0.11 adducts/107 dA). Collectively, the results of the tissue distribution and pharmacokinetic analysis may not fully support our hypothesis, but the capacity of the target organs vs nontarget organs to metabolize DBP to active intermediates that can damage DNA may account for its tissue selective tumorigenicity.