Beach A C, Agarwal S C, Lambert G R, Nesnow S, Gupta R C
Graduate Center for Toxicology, University of Kentucky, Lexington 40506.
Carcinogenesis. 1993 Apr;14(4):767-71. doi: 10.1093/carcin/14.4.767.
Cyclopenta[c,d]pyrene (CPP) is a widespread polycyclic aromatic hydrocarbon with potent mutagenic and carcinogenic activity. The trans isomer of 3,4-dihydro-3,4-dihydroxy-cyclopenta[c,d]pyrene has been shown to be the major metabolic product of CPP in rat, mouse or human microsomal systems, as well as in peroxyl radical-generating systems, indicating the preferential formation of its obligatory precursor, CPP-3,4-epoxide. The direct mutagenicity of CPP-3,4-epoxide, the inactivity of 3,4-dihydro-CPP and the DNA adduct forming capacity of CPP in vivo has prompted analysis of the DNA adducts produced by CPP-3,4-epoxide to provide information pertaining to: (i) the role this postulated major ultimate mutagenic metabolite may play in the formation of DNA adducts in vivo; (ii) the base selectivity of CPP-3,4-epoxide DNA adducts; and (iii) the role of CPP-3,4-epoxide in the mutagenicity/carcinogenicity of CPP. CPP-3,4-epoxide was reacted with calf thymus DNA, dGp, dAp, dTp, dCp, poly dG-dC, poly dA-dT and poly dG. Adducts were analyzed by the butanol-enhanced version of 32P-postlabeling. Four major and at least three minor adducts formed with DNA in vitro, which were further analyzed for their base selectivity. A similar spectrum of adducts was exhibited by dGp, poly dG-dC and poly dG. dCp, dTp, and dAp formed one, two, and four adducts respectively. The relative binding in adducts per 10(7) nucleotides was in the following descending order: dGp (6000), poly dG-dC (5800), dTp (5300), dAp (4800), calf thymus DNA (3800), poly dA-dT (2300), poly dG (2600) and dCp (20). Adducts derived from either dGp, poly dG-dC or poly dG co-migrated with the DNA adducts in three solvent systems, indicating that CPP-3,4-epoxide forms DNA adducts almost exclusively with deoxyguanosine.
环戊并[c,d]芘（CPP）是一种广泛存在的多环芳烃，具有强大的致突变和致癌活性。3,4 - 二氢 - 3,4 - 二羟基 - 环戊并[c,d]芘的反式异构体已被证明是CPP在大鼠、小鼠或人类微粒体系统以及过氧自由基生成系统中的主要代谢产物，这表明其必需前体CPP - 3,4 - 环氧化物优先形成。CPP - 3,4 - 环氧化物的直接致突变性、3,4 - 二氢 - CPP的无活性以及CPP在体内形成DNA加合物的能力，促使人们对CPP - 3,4 - 环氧化物产生的DNA加合物进行分析，以提供有关以下方面的信息：（i）这种假定的主要最终致突变代谢产物在体内DNA加合物形成中可能起的作用；（ii）CPP - 3,4 - 环氧化物DNA加合物的碱基选择性；（iii）CPP - 3,4 - 环氧化物在CPP的致突变性/致癌性中的作用。CPP - 3,4 - 环氧化物与小牛胸腺DNA、dGp、dAp、dTp、dCp、聚dG - dC、聚dA - dT和聚dG反应。通过丁醇增强版的32P后标记法分析加合物。在体外与DNA形成了四种主要加合物和至少三种次要加合物，并进一步分析了它们的碱基选择性。dGp、聚dG - dC和聚dG表现出相似的加合物谱。dCp、dTp和dAp分别形成了一种、两种和四种加合物。每10^7个核苷酸中加合物的相对结合量按以下降序排列：dGp（6000）、聚dG - dC（5800）、dTp（5300）、dAp（4800）、小牛胸腺DNA（3800）、聚dA - dT（2300）、聚dG（2600）和dCp（20）。源自dGp、聚dG - dC或聚dG的加合物在三种溶剂系统中与DNA加合物共迁移，表明CPP - 3,4 - 环氧化物几乎只与脱氧鸟苷形成DNA加合物。
