Tumorigenicity and liver tumor ras-protooncogene mutations in CD-1 mice treated neonatally with 1- and 3-nitrobenzo[a]pyrene and their trans-7,8-dihydrodiol and aminobenzo[a]pyrene metabolites.
The environmental pollutants 1- and 3-nitrobenzo[a]pyrene (1- and 3-NBaP) are metabolized by mammalian microsomes through ring oxidation to 1-NBaP trans-7,8-dihydrodiol and 3-NBaP trans-7,8-dihydrodiol, and by nitroreduction to 1- and 3-aminobenzo[a]pyrene. To determine if these compounds are tumorigenic, 1- and 3-NBaP, along with several of their metabolites and the parent benzo[a]pyrene (BaP) and its trans-7,8-dihydrodiol metabolite, were tested in the neonatal CD-1 mouse bioassay. Male mice were administered i.p. injections at a total dose of 100 or 400 nmol per mouse on 1, 8 and 15 days after birth. While the liver tumor incidences for BaP, BaP trans-7,8-dihydrodiol, and the positive control 6-nitrochrysene (6-NC) were significantly higher than in the solvent control animals, all the other tested compounds exhibited no tumorigenicity. The frequency of Ha- and Ki-ras mutations in liver tumors of mice treated with BaP, BaP trans-7,8-dihydrodiol, and 6-NC were higher than in the few liver tumors isolated from control mice or mice treated with the NBaPs or their metabolites. Since 1- and 3-NBaP and their metabolites are potent mutagens in the Salmonella assay and moderate mutagens in the Chinese hamster ovary (CHO) mammalian mutagenicity assay, our results indicate that the in vitro mutagenicity of these compounds does not correlate with their tumorigenicity.
Von Tungeln
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Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Xia
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Bucci
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Heflich
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Fu
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D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001564:Benzo(a)pyrene / Q000633:toxicity; D001580:Benzopyrenes / Q000633:toxicity*; D015197:Carcinogenicity Tests; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics; D002911:Chrysenes / Q000633:toxicity; D004252:DNA Mutational Analysis; D004101:Dihydroxydihydrobenzopyrenes / Q000633:toxicity; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects
C119862:1-nitrobenzo(a)pyrene-trans-7,8-dihydrodiol; C119863:3-nitrobenzo(a)pyrene-trans-7,8-dihydrodiol; D001580:Benzopyrenes; D002911:Chrysenes; D004101:Dihydroxydihydrobenzopyrenes; D009153:Mutagens; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; C042055:3-nitrobenzo(a)pyrene; C040217:1-nitrobenzo(a)pyrene; C035986:6-nitrochrysene; C119864:1-aminobenzo(a)pyrene; C119865:3-aminobenzo(a)pyrene