Cytotoxicity, cellular transformation and DNA adducts in normal human diploid fibroblasts exposed to 1-nitrosopyrene, a reduced derivative of the environmental contaminant, 1-nitropyrene.
Treatment of normal human diploid fibroblasts with 0.3-22 microM 1-nitrosopyrene resulted in a dose-dependent decrease in relative cloning efficiency and an increase in anchorage-independent growth in soft agar. When compared to previous experiments, 1-nitrosopyrene was 10- to 20-fold more cytotoxic and 5- to 10-fold more potent at inducing morphological transformation than 1-nitropyrene. Incubation of the fibroblasts with 8 microM 1-nitropyrene in the presence of xanthine oxidase, a mammalian nitroreductase, resulted in the formation of one major DNA adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene, at a level of 1.1 adducts per 10(6) nucleotides. Fibroblasts treated with 1-nitrosopyrene formed the same DNA adduct; however, only a 0.3 microM concentration was required to give 0.7 adducts per 10(6) nucleotides in the fibroblast DNA. These data indicate that a limiting step in the cellular toxicity and transformation of normal human diploid fibroblasts by 1-nitropyrene is the initial reduction to 1-nitrosopyrene.
D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D011721:Pyrenes / Q000378:metabolism / Q000633:toxicity*; D014316:Tritium
D011721:Pyrenes; D014316:Tritium; C044707:1-nitrosopyrene; D004247:DNA