Differences in metabolic activation of dibenzo[a,e]fluoranthene characterized by 32P-postlabeling in two mouse fibroblast models.
The formation of DNA adducts was investigated in mouse fibroblasts from two different tissues--embryos and adult lung--after incubation with dibenzo[a,e]fluoranthene (DBF) or its major proximate metabolites. The nuclease P1 modification of the 32P-postlabeling method was adapted for detection of DBF-DNA adducts. Quantitative and qualitative differences were observed in the metabolic activation mediated by the two cell types. DBF-DNA adducts generated three major spots reproducibly, and more than ten spots of medium or weak importance. The highest level of DNA binding occurred via the DBF-bay region vicinal dihydrodiol epoxide but with significant differences in the quantitative distribution of adducts. Striking qualitative differences were observed when lung fibroblasts were incubated with the DBF-pseudo bay region dihydrodiol (DBF-12,13-DHD). The spots representing adducts induced in embryo fibroblasts by DBF-3OH-12,13-DHD, a further metabolite of DBF-12,13-DHD, were totally absent from chromatograms of lung cells. These results show that both embryo and lung fibroblasts can activate DBF but that different cytochrome P-450 forms and substrate affinities are involved. The finding that different activation systems may be present in subcategories of the same tissue, may provide a partial explanation for the wide variations in sensitivity to carcinogens among species, organs and tissues.
Périn-Roussel
O
O
Unité de Recherche sur la Prolifération Cellulaire et la Cancérogénèse (CNRS-URA 1343) Institut Curie, Centre Universitaire, Orsay, France.
Barat
N
N
Plessis
M J
MJ
Zajdela
F
F
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005449:Fluorenes / Q000378:metabolism / Q000493:pharmacokinetics*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009153:Mutagens / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010761:Phosphorus Radioisotopes
D002273:Carcinogens; D005449:Fluorenes; D009153:Mutagens; D010761:Phosphorus Radioisotopes; C037249:12,13-dihydro-12,13-dihydroxydibenzo(a,e)fluoranthene; C041400:3,4-dihydro-3,4-dihydroxydibenzo(a,e)fluoranthene; C012888:dibenzo(a,e)fluoranthene; D004247:DNA; D010105:Oxygenases; D004121:Dimethyl Sulfoxide