Carcinogenesis, Vol 19, 1829-1836, Copyright © 1998 by Oxford University Press
MM Manson, EA Hudson, HW Ball, MC Barrett, HL Clark, DJ Judah, RD Verschoyle and GE Neal
Indole-3-carbinol (I3C) was examined for its ability to inhibit aflatoxin
B1 (AFB1)-induced hepatocarcinogenesis in male Fischer rats when
administered either before or after the carcinogen. After 13 weeks, animals
pretreated with I3C (0.5% in the diet) for 2 weeks prior to administration
of AFB1 and with continuing treatment during exposure to the carcinogen
were protected from development of preneoplastic lesions, as determined by
the classical markers gamma- glutamyltranspeptidase (GGT) and glutathione
S-transferase (GST) P. In animals receiving AFB1 for 6 weeks before
treatment with I3C, there was no obvious protective effect at 13 weeks
compared with animals receiving only AFB1. Using cytokeratin 18 expression
as a marker, animals fed AFB1 alone had a small number of positive foci at
13 weeks. However, no cytokeratin-positive foci were visible in the
majority of livers from either group receiving I3C in combination with AFB1
and after 43 weeks all animals in these groups were protected from liver
tumour formation. These results suggest that expression of cytokeratin 18,
a later phenotypic change in foci than induction of GST-P and GGT,
correlates more closely with tumour outcome in this model. I3C appeared to
retard progression of AFB1-induced carcinogenesis at both the initiation
and promotion stages. Continuous treatment with I3C for 13 weeks caused
significant induction of CYP1A1, 1A2, 3A and 2B1/2, GST Yc2, aflatoxin B1
aldehyde reductase and quinone reductase. Such alteration of the drug
metabolizing capacity of the liver by I3C contributes to blocking of
initiation, while the observed inhibition of ornithine decarboxylase, a
rate limiting enzyme in polyamine biosynthesis, and of tyrosine kinase
activity may contribute to the suppressive effect of I3C.
ARTICLES
Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3- carbinol in rat liver--predicting the outcome using early biomarkers
MRC Toxicology Unit, University of Leicester, UK. mmm2@le.ac.uk
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