MECHANISMS OF INDOLE-3-CARBINOL (I3C) ANTICARCINOGENESIS - INHIBITIONOF AFLATOXIN B-1-DNA ADDUCTION AND MUTAGENESIS BY I3C ACID CONDENSATION PRODUCTS

Possible inhibitory mechanisms of indole-3-carbinol (I3C) against afla toxin B-1 (AFB(1)), a potent hepatocarcinogen, were examined in rainbo w trout. In the Salmonella assay using a trout post-mitochondrial acti vation system, I3C itself was not an antimutagen against AFB(1). The s tudy also evaluated: the antimutagenic ability of I3C oligomers; an ac id reaction mixture (RXM) of I3C, generated at low pH to simulate I3C products formed under acidic conditions of the stomach; 3,3-diindolylm ethane (I33'), the major derivative of I3C found in trout liver; and , 11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b '']triindole, the cy clic trimer of I3C (CT), a derivative of I3C in liver and one of the m ajor components of RXM. Concentrations of 3.5 mu M and greater of I33' , CT or RXM showed about 80% inhibition compared with the control. Hig her concentrations (70 mu M) of the various I3C oligomers also inhibit ed (to a maximum of 55%) mutagenesis of synthetic AFB(1)-8,9-epoxide a dded to the Salmonella assay, in the absence of activating enzymes. I3 3' inhibited total microsome catalysed AFB(1)-DNA binding in vitro in an apparently non-competitive manner (K-is = 27.6 +/- 9.4 mu M, K-ii = 37.5 +/- 32.2 mu M). These results suggest that the anticarcinogenic effect of I3C against AFB(1) in rainbow trout, and perhaps other speci es, is due in part to inhibition of AFB, bioactivation enzymes and to scavenging of the activated AFB(1)-8,9-epoxide.