Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline-DNA adducts by indole-3-carbinol: dose-response studies in the rat colon

Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant cryptfoci and DNA adducts in rats given heterocyclic amine colon carcinogens,such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Mechanism studiesindicate that I3C induces cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2),isozymes that respectively metabolize IQ via ring hydroxylation or activatethe carcinogen by N-hydroxylation. The present study examined thedose-response for induction of CYP1A1 versus CYP1A2 by I3C, and comparedthe profiles of induction with the dose- response for inhibition of IQ-DNAadducts in the colon of the F344 rat. Dietary equivalent doses of I3C inthe range 100-1000 p.p.m. increased in a dose-related manner bothethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase(MROD) activities in the liver and colonic mucosa, and Western blots showeda corresponding induction of CYP1A1 and CYP1A2 proteins. However, dietaryequivalent doses of I3C in the range 10-25 p.p.m. (i) reduced hepatic ERODand MROD activities and CYP1A protein levels compared with controls, (ii)increased the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to amore potent mutagen when liver microsomes from rats given I3C were used formetabolic activation in the Salmonella assay. Rats given a single oral doseof I3C shortly before administering IQ (5 mg/kg body wt, p.o.) exhibiteddose-related inhibition of colonic IQ-DNA adducts in the range 25-100p.p.m. I3C, reaching 95% inhibition at doses > or = 100 p.p.m. I3C, butIQ-DNA adducts were elevated slightly at the lowest I3C dose as comparedwith the controls. The possible significance of the low versus high doseeffects of I3C are discussed in the context of human dietary exposures toI3C and the reported chemopreventive mechanisms of I3C in vivo.