Carcinogenesis, Vol 18, 2149-2153, Copyright © 1997 by Oxford University Press
M Xu, HA Schut, LF Bjeldanes, DE Williams, GS Bailey and RH Dashwood
Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant crypt
foci and DNA adducts in rats given heterocyclic amine colon carcinogens,
such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Mechanism studies
indicate that I3C induces cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2),
isozymes that respectively metabolize IQ via ring hydroxylation or activate
the carcinogen by N-hydroxylation. The present study examined the
dose-response for induction of CYP1A1 versus CYP1A2 by I3C, and compared
the profiles of induction with the dose- response for inhibition of IQ-DNA
adducts in the colon of the F344 rat. Dietary equivalent doses of I3C in
the range 100-1000 p.p.m. increased in a dose-related manner both
ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase
(MROD) activities in the liver and colonic mucosa, and Western blots showed
a corresponding induction of CYP1A1 and CYP1A2 proteins. However, dietary
equivalent doses of I3C in the range 10-25 p.p.m. (i) reduced hepatic EROD
and MROD activities and CYP1A protein levels compared with controls, (ii)
increased the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to a
more potent mutagen when liver microsomes from rats given I3C were used for
metabolic activation in the Salmonella assay. Rats given a single oral dose
of I3C shortly before administering IQ (5 mg/kg body wt, p.o.) exhibited
dose-related inhibition of colonic IQ-DNA adducts in the range 25-100
p.p.m. I3C, reaching 95% inhibition at doses > or = 100 p.p.m. I3C, but
IQ-DNA adducts were elevated slightly at the lowest I3C dose as compared
with the controls. The possible significance of the low versus high dose
effects of I3C are discussed in the context of human dietary exposures to
I3C and the reported chemopreventive mechanisms of I3C in vivo.
ARTICLES
Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline-DNA adducts by indole-3-carbinol: dose-response studies in the rat colon
Department of Environmental Biochemistry, University of Hawaii, Honolulu 96822, USA.
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