Mechanisms of anti-carcinogenesis by indole-3-carbinol: detailed in vivo DNA binding dose-response studies after dietary administration with aflatoxin B1

Abstract

Several recent reports have described inhibitor-mediated reductions in the covalent binding of various carcinogens to DNA in vivo. The majority of these studies show inhibitory effects after testing at one inhibitor and one carcinogen dose level only. Consequently,the detailed relationships between inhibitor dose, carcinogen dose, and in vivo inhibitory potency have not been clearly delineated in any species. To systematically determine these relationships in vivo, rainbow trout (Salmo gairdneri) were exposed to a range of carcinogen (aflatoxin B1, AFB1) and inhibitor (indole-3-carbinol, I3C) doses by concomitant dietary exposure. Inhibitory potencies were then assessed using in vivo covalent binding of AFB1 to hepatic DNA as an end-point. Linear increases in DNA binding occurred with increasing dose of AFB1 and with time of inhibitor/carcinogen co-treatment, at each I3C dose level. Successive increases in inhibitor dose resulted in corresponding dose-related decreases in AFB1-DNA binding such that a series of curves of decreasing slope was produced. AFB1-DNA binding was suppressed by almost 95% at the highest I3C dose tested. Thesestudies describe for the first time such a degree of inhibition by I3C on covalent binding of AFB1 to DNA in vivo, where inhibitor and carcinogen are covariables administered repeatedly in the diet. Moreover, the linear inhibitory response observed at low I3C doses indicates the possible absence of any significant threshold for I3C protection against AFB1-DNA binding. Thus, even at low levels I3C may offer some protection against chemically-induced neoplasia.