Comparison of blood protein and target organ DNA and protein binding following topical application of benzo[a]pyrene and 7H-dibenzo[c,g]carbazole to mice.
7H-Dibenzo[c,g]carbazole (DBC) induces skin and liver tumors in mice following topical application, whereas benzo[a]pyrene (BP) induces only skin tumors. DBC also binds to liver DNA to a much greater extent than does BP. The present study examined factors that might account for the difference in DNA binding activity. [3H]DBC was applied topically to CD-1 mice at doses of 15, 100 and 1000 nmol/mouse and tissues and blood samples were taken 24 h later. Absorption of DBC from skin into blood and binding to blood proteins occurred linearly with dose. DBC bound to albumin at a 50-fold higher level than to globin and levels of albumin adducts showed good correlation with levels of DNA adducts in liver. Hepatic preference over skin in DNA binding was found to be dose-dependent. For comparison of [3H]BP and [3H]DBC binding, doses of 1000 nmol/mouse were used and the mice were sacrificed at 12, 24 and 48 h. The rate of DBC uptake from skin was 70% higher than for BP over the first 24 h, which was reflected in 40-50% higher plasma levels of DBC radiolabel. Skin protein and DNA binding were 2- to 5-fold higher for BP than DBC. Conversely, total 3H radioactivity levels in liver were 2- to 3-fold higher and liver DNA and protein binding were 15- to 20-fold and 3- to 5-fold higher respectively for DBC. Blood protein adduct levels were similar for both chemicals, suggesting that DBC metabolites formed in the liver were too reactive to re-enter the systemic circulation. Only minor amounts of the radiolabel in the liver were present as the parent compounds by 12 h after dosing. These results indicate that more rapid absorption from skin and selective accumulation in the liver contribute to the greater liver DNA binding seen with DBC, but the types of liver metabolites appear to be the major factor accounting for the binding difference.
Environmental Monitoring Systems Laboratory, US Environmental Protection Agency, Cincinnati, OH 45268.
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JR
Meier
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Warshawsky
D000085:Acetates; D000287:Administration, Topical; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D002227:Carbazoles / Q000378:metabolism* / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism*; D012869:Skin Absorption; D014018:Tissue Distribution; D014020:Tissue Extracts / Q000032:analysis; D014316:Tritium
D000085:Acetates; D001798:Blood Proteins; D002227:Carbazoles; D002273:Carcinogens; D006454:Hemoglobins; D012709:Serum Albumin; D014020:Tissue Extracts; D014316:Tritium; D001564:Benzo(a)pyrene; C007650:ethyl acetate; D004247:DNA; C013478:7H-dibenzo(c,g)carbazole