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
Ls. Von Tungeln et al., 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, CANCER LETT, 137(2), 1999, pp. 137-143
The environmental pollutants 1- and 3-nitrobenzo[a]pyrene (1- and 3-NBaP) a
re metabolized by mammalian microsomes through ring oxidation to 1-NBaP tra
ns-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 tumori
genic, 1- and 3-NBaP, along with several of their metabolites and the paren
t benzo[a]pyrene (BaP) and its trans-7,8-dihydrodiol metabolite, were teste
d in the neonatal CD-I mouse bioassay. Male mice were administered i.p, inj
ections at a total dose of 100 or 400 nmol per mouse on 1, 8 and 15 days af
ter birth. While the liver tumor incidences for BaP, BaP trans-7,8-dihydrod
iol, and the positive control 6-nitrochrysene (6-NC) were significantly hig
her than in the solvent control animals, all the other tested compounds exh
ibited no tumorigenicity. The frequency of Ha- and Ki-ras mutations in live
r 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 tre
ated with the NBaPs or their metabolites. Since 1- and 3-NBaP and their met
abolites are potent mutagens in the Salmonella assay and moderate mutagens
in the Chinese hamster ovary (CHO) mammalian mutagenicity assay, our result
s indicate that the in vitro mutagenicity of these compounds does not corre
late with their tumorigenicity. (C) 1999 Published by Elsevier Science Ltd.
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