Carcinogenicity, DNA adduct formation and K-ras activation by 7H-dibenzo[c,g]carbazole in strain A/J mouse lung.
Carcinogenicity, DNA adduct formation and K-ras activation by 7H-dibenzo[c,g]carbazole in strain A/J mouse lung.
复制标题
7H-二苯并[c,g]咔唑在 A/J 品系小鼠肺中的致癌性、DNA 加合物形成和 K-ras 激活。
DOI：
10.1093/carcin/17.4.865
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发表时间：
1996
期刊：
影响因子：
4.7
通讯作者：
Stoner,G
中科院分区：
文献类型：
--
作者：
Warshawsky,D;Talaska,G;Jaeger,M;Collins,T;Galati,A;You,L;Stoner,G
N-杂环多核芳香烃 (NHA) 是有机材料燃烧过程中形成的环境污染物。7H-二苯并[c,g]咔唑 (DBC) 是肺、肝和皮肤的强致癌物。我们进行这些研究是为了确定A/J品系小鼠中DBC肺癌致癌性的组织特异性是否通过肺组织中DBC-DNA加合物的形成来反映，以及这些加合物是否与K-rasgene中的突变模式一致。 A/J 品系小鼠接受单次腹膜内注射。 以0、5、10、20或40mg/kg的剂量注射DBC，并在第1、3、5、7、14和21天通过32P后标记监测肺中DNA加合物的水平。在DBC治疗后8个月处死剩余的动物，并测定肺肿瘤的多样性和肿瘤中的K突变模式。肺肿瘤对 DBC 的反应与剂量相关，5 mg/kg 时平均为 4.7 ± 1.2 个肿瘤/小鼠，40 mg/kg 时为 48.1 ± 5.5 个肿瘤/小鼠。在肺中观察到多达 7 个 DBC-DNA 加合物。肺部 DNA 结合水平最高为 40 mg/kg，最大结合时间为 5-7 天。在较低剂量水平下，与 DNA 的最大结合减少并转移到较早的时间点。肺中在所有剂量水平下结合水平最高的 DBC-DNA 加合物是 DBC-DNA 加合物 3。肺中 K-rasgene 中 DBC 诱导的大多数突变是密码子 61 第三个碱基的 A↑T(80%) 颠换，这种突变以前在 A/J 品系小鼠的化学诱导肺肿瘤中未观察到。
N-Heterocyclic polynuclear aromatic hydrocarbons (NHA) are environmental pollutants formed during the combustion of organic materials.7H-Dibenzo[c,g]carbazole (DBC) is a potent carcinogen in lung, liver and skin. We undertook these studies to determine whether tissue specificity for DBC lung carcinogenicity inthe strain A/J mouse is mirrored by formation of DBC-DNA adducts in lung tissue and whether these adducts are consistent with mutation patterns in the K-rasgene. Strain A/J mice were given a single i.p. injectionof DBC at doses of 0, 5, 10, 20 or 40 mg/kg and levels of DNA adducts in the lung were monitored by32P-postlabeling on days 1,3,5,7,14 and 21. The remaining animals were sacrificed 8 months after DBC treatment and lung tumor multiplicity and K-rasmutation patterns in the tumors were determined. The lung tumor response to DBC was dose related, with an average of 4.7 ± 1.2 tumors/mouse at 5 mg/kg and 48.1 ± 5.5 tumors/mouse at 40 mg/kg. As many as seven DBC-DNA adducts were observed in the lung. DNA binding levels in the lung were highest at 40 mg/kg, with maximum binding at 5-7 days. At lower dose levels the maximum binding to DNA decreased and shifted to earlier time points. The DBC-DNA adduct in the lung with the highest level of binding at all dose levels was DBC-DNA adduct 3. The majority of DBC-induced mutations in the K-rasgene in the lung were A↑T(80%) transversions in the third base of codon 61, a mutation that has not been previously observed in chemically induced lung tumors in strain A/J mice.