IN-VIVO MUTAGENICITY AND DNA ADDUCT LEVELS OF HETEROCYCLIC AMINES IN MUTA(TM) MICE AND C-MYC LACZ DOUBLE TRANSGENIC MICE/

Citation
Cd. Davis et al., IN-VIVO MUTAGENICITY AND DNA ADDUCT LEVELS OF HETEROCYCLIC AMINES IN MUTA(TM) MICE AND C-MYC LACZ DOUBLE TRANSGENIC MICE/, Mutation research, 356(2), 1996, pp. 287-296
Citations number
32
Categorie Soggetti
Genetics & Heredity",Biology,"Biothechnology & Applied Migrobiology
Journal title
ISSN journal
00275107
Volume
356
Issue
2
Year of publication
1996
Pages
287 - 296
Database
ISI
SICI code
0027-5107(1996)356:2<287:IMADAL>2.0.ZU;2-B
Abstract
The cooked meat derived heterocyclic amines (HCAs) 2-amino-3-methylimi dazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxali ne (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (A alpha C) are establi shed mutagens in the Salmonella assay and hepatocarcinogens in mice. T he current study uses transgenic mice to examine hepatic HCA-DNA adduc t formation and mutagenesis in vivo and the impact of hepatic overexpr ession of the c-myc oncogene on HCA-induced mutagenesis. C57B1/lacZ an d c-myc/lacZ mice strains, produced by crossbreeding Muta(TM)Mice (car rying the lacZ mutation target gene) with either C57B1 control or c-my c transgenic mice, respectively, were treated with 10 daily doses of I Q, MeIQx or A alpha C (20 mu g/g, p.o.). Four weeks after dosing, the frequency of mutations in the lacZ gene in liver of either C57B1/lacZ or c-myc/lacZ mice was significantly higher in mice treated with any o ne of the three HCAs than in mice given vehicle only. In addition, all three HCAs formed hepatic DNA adducts, as measured by the P-32-postla beling analysis 24 h after dosing. In both strains of mice, hepatic DN A adduct levels were 2-3-fold higher with A alpha C than with either I Q or MeIQx, although the mutant frequencies in the lacZ gene were 30-4 0% lower in mice dosed with A alpha C. These results suggest that A al pha C-DNA adducts may be less mutagenic in vivo than either IQ- or MeI Qx-DNA adducts. The lacZ mutant frequencies observed with all three HC As appeared to be influenced by c-myc transgene expression: after HCA treatment, transgenic mice carrying the c-myc gene showed a 30-40% hig her lacZ mutant frequency than mice not carrying this transgene. Notab ly, lacZ mutant frequencies were not different among C57B1/lacZ and c- myc/lacZ mice that received vehicle control. DNA adduct studies showed that the levels of IQ- and MeIQx-DNA adducts were 2-3-fold higher in c-myc/lacZ mice than in C57B1/lacZ mice; however, A alpha C-DNA adduct s were not statistically different between the two strains. In additio n, phase I metabolic activation of these HCAs, as assessed by hepatic microsomal mutagenic activation, was also similar in both strains of m ice. These results support the notion that overexpression of the c-myc oncogene cooperates with the HCAs to enhance in vivo mutagenicity. Fu rther studies are needed to assess the mechanisms of this cooperative effect.