Prahalad A K, Ross J A, Nelson G B, Roop B C, King L C, Nesnow S, Mass M J
National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Carcinogenesis. 1997 Oct;18(10):1955-63. doi: 10.1093/carcin/18.10.1955.
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.
二苯并[a,l]芘（DB[a,l]P）是一种环境多环芳烃，是在小鼠皮肤和大鼠乳腺中测试过的最具致癌性的物质。在本研究中，检测了DB[a,l]P在A/J品系小鼠肺中的DNA加合物形成、致瘤性以及肿瘤DNA中Ki-ras癌基因突变的诱导情况。将小鼠分组，经腹腔单次注射0.3、1.5、3.0或6.0mg/kg的DB[a,l]P（溶于三辛酸甘油酯中）。处理后，在1至28天之间的不同时间测量DNA加合物，在250天时计数肿瘤，并分析Ki-ras癌基因第12和61密码子中的点突变情况。DB[a,l]P在A/J品系小鼠肺中诱导出六种主要和四种次要的DNA加合物。加合物水平在注射后5至10天达到最高，随后逐渐下降。肺组织中的DB[a,l]P-DNA加合物来源于反式和顺式-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），并且通过共色谱法显示DNA中的脱氧腺苷（dAdo）和脱氧鸟苷（dGuo）残基均参与其中。主要加合物被鉴定为反式-DB[a,l]PDE与DNA中的dAdo反应的产物。DB[a,l]P以剂量依赖性方式诱导出大量肺腺瘤，最高剂量（6.0mg/kg）时每只小鼠产生16.1个腺瘤。在经三辛酸甘油酯处理的对照动物中，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DNA加合物水平的函数，DB[a,l]P诱导肺腺瘤的效力与其他多环芳烃大致相同，这表明在A/J品系小鼠肺模型中，DB[a,l]P形成的加合物在致癌效力上与其他多环芳烃相似。对DB[a,l]P诱导的肺肿瘤中Ki-ras突变谱的分析表明，主要突变是第12密码子第一个碱基的G→T颠换、第12密码子第二个碱基的A→G转换以及第61密码子第二个或第三个碱基的A→T颠换，这与DNA加合物谱一致。
