Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung
Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung
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DOI：
10.1093/carcin/18.10.1955
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发表时间：
1997-10-01
期刊：
影响因子：
4.7
通讯作者：
Mass, MJ
中科院分区：
文献类型：
--
作者：
Prahalad, AK;Ross, JA;Mass, MJ
二苯并[a，l]芘（DB[a，l]P）是一种环境多环芳烃，是小鼠皮肤和大鼠乳腺中最强的致癌物。在这项研究中，DB[a，l]P的DNA加合，致瘤性，并诱导Ki-ras癌基因突变的肿瘤DNA在菌株A/J小鼠肺。各组小鼠接受单次腹膜内注射0.3、1.5、3.0或6.0 mg/kg DB[a，l]P的三辛酸甘油酯溶液。治疗后，在1至28天之间的时间测量DNA加合物，而在250天时计数肿瘤并分析Ki-ras癌基因密码子12和61中点突变的发生。DB[a，l]P在A/J系小鼠肺中诱导了六种主要和四种次要的DNA加合物。最大水平的内收发生在注射后5至10天，随后逐渐减少。肺组织中DB[a，l]P-DNA加合物来源于DNA中的反式和顺式-11，12-二羟基-13，14-环氧-11，12，13，14-四氢二苯并[a，l]芘（DB[a，l]PDE）以及脱氧腺苷（dAdo）和脱氧鸟苷（dGuo）残基。DB[a，l]P以剂量依赖性方式诱导显著数量的肺腺瘤，最高剂量（6.0 mg/kg）产生16.1个腺瘤/小鼠。在tricaprylin给药对照动物中，每只小鼠有0.67个腺瘤。基于给药剂量，DB[a，l]P比包括苯并[a]芘在内的其他环境致癌物更具活性。作为时间积分的DNA加合物水平的函数，DB[a，l]P诱导肺腺瘤具有与其他多环芳烃大致相同的效力，这表明DB[a，l]P形成的加合物在A/J小鼠肺模型中与其他多环芳烃的致癌效力相似。DB[a，l] P诱发的肺癌Ki-ras基因突变谱分析显示，其主要突变为密码子12第一个碱基的G →>T颠换，密码子12第二个碱基的A →>G颠换，密码子61第二或第三个碱基的A →>T颠换，与DNA加合物谱一致。
Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hydrocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction, tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in strain A/J mouse lung. Groups of mice received a single i.p. injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occurrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days after injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and syn-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatography The major adduct was identified as a product of the reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbers of lung adenomas in a dose-dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens including benzo[a]pyrene. As a function of time-integrated DNA adduct levels, DB[a,l]P induced lung adenomas with about the same potency as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar in carcinogenic potency to other PAHs in the strain A/J mouse lung model. Analysis of the Ki-ras mutation spectrum in DB[a,l]P-induced lung tumors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of codon 12, and A-->T transversions in the second or third base of codon 61, concordant with the DNA adduct profile.