Nesnow S, Ross J A, Mass M J, Stoner G D
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
Exp Lung Res. 1998 Jul-Aug;24(4):395-405. doi: 10.3109/01902149809087376.
This paper describes a series of studies on the lung tumorigenic activities of polycyclic aromatic hydrocarbons (PAHs) in strain A/J mice, their ability to form PAH-DNA adducts in lung tissues, and their ability to mutate the Ki-ras oncogene in PAH-induced tumors. Seven PAHs were studied: cyclopenta[cd]pyrene (CPP), benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), dibenz[a,h] anthracene (DBA), 5-methylchrysene (5MC), benz[j]aceanthrylene (B[j]A), and dibenzo[a,l]pyrene (DB[a,l]P). The dose-response data for the PAHs revealed 100-fold differences in tumor potency based on dose, with the order of activity DB[a,l]P, DBA > B[j]A > 5MC > CPP B[a]P > B[b]F. Large differences in tumor multiplicity were also observed between the PAHs. DNA adducts were measured by 32P-postlabeling techniques on DNA from lungs of mice treated with these PAH's. DB[a,l]P gave syn- and anti-fjord-region diol-epoxide adducts of dAdo and dGuo; DBA gave both bay-region diol-epoxide-dGuo and bisdihydrodiol-epoxide adducts; CPP gave cyclopenta-ring-dGuo adducts; B[j]A gave a mixture of cyclopenta-ring-dGuo and -dAdo adducts; 5MC gave anti-bay-region diol-epoxide-dGuo adducts; B[a]P gave bay-region diol-epoxide-dGuo adducts; and B[b]F gave 5-hydroxy-B[b]F-diol-epoxide-dGuo adducts. Ki-ras codon 12 and 61 mutation analysis of PAH induced tumors was performed using PCR and dideoxy sequencing methods. DB[a,l]P gave both codon 12 and codon 61 mutations. High proportions of codon 12 TGT mutations from B[a]P-, B[b]F- and 5MC-, induced tumors and CGT mutations from CPP- and B[j]A-induced tumors were observed. DBA produced no mutations in Ki-ras codons 12 or 61 by direct sequencing. The interrelationships between the tumorigenesis, DNA adduct, and oncogene mutation data are discussed.
本文描述了一系列关于多环芳烃（PAHs）在A/J品系小鼠中的肺致癌活性、它们在肺组织中形成PAH-DNA加合物的能力以及它们在PAH诱导的肿瘤中使Ki-ras癌基因突变的能力的研究。研究了七种PAHs：环戊并[cd]芘（CPP）、苯并[a]芘（B[a]P）、苯并[b]荧蒽（B[b]F）、二苯并[a,h]蒽（DBA）、5-甲基屈（5MC）、苯并[j]荧蒽（B[j]A）和二苯并[a,l]芘（DB[a,l]P）。PAHs的剂量反应数据显示，基于剂量的肿瘤效力存在100倍的差异，活性顺序为DB[a,l]P、DBA > B[j]A > 5MC > CPP、B[a]P > B[b]F。在PAHs之间也观察到肿瘤多样性的巨大差异。通过32P后标记技术对用这些PAHs处理的小鼠肺组织中的DNA进行DNA加合物测量。DB[a,l]P产生了dAdo和dGuo的顺式和反式峡区二醇环氧化物加合物；DBA产生了湾区二醇环氧化物-dGuo和双二氢二醇环氧化物加合物；CPP产生了环戊环-dGuo加合物；B[j]A产生了环戊环-dGuo和-dAdo加合物的混合物；5MC产生了反式湾区二醇环氧化物-dGuo加合物；B[a]P产生了湾区二醇环氧化物-dGuo加合物；B[b]F产生了5-羟基-B[b]F-二醇环氧化物-dGuo加合物。使用PCR和双脱氧测序方法对PAH诱导的肿瘤进行Ki-ras密码子12和61突变分析。DB[a,l]P产生了密码子12和密码子61突变。观察到来自B[a]P、B[b]F和5MC诱导的肿瘤中高比例的密码子12 TGT突变以及来自CPP和B[j]A诱导的肿瘤中的CGT突变。通过直接测序，DBA在Ki-ras密码子12或61中未产生突变。讨论了肿瘤发生、DNA加合物和癌基因突变数据之间的相互关系。
