Potency of dietary indole-3-carbinol as a promoter of aflatoxin B-1-initiated hepatocarcinogenesis: results from a 9000 animal tumor study

Indole-3-carbinol (I3C), a metabolite of glucobrassicin found in cruciferou s vegetables, is documented as acting as a modulator of carcinogenesis and, depending on timing and dose of administration, it may promote hepatocarci nogenesis in some animal models. In this study we demonstrate that, when gi ven post-initiation, dietary I3C promotes aflatoxin B-1 (AFB(1))-induced he patocarcinogenesis in the rainbow trout model at levels as low as 500 p.p.m . Trout embryos (similar to 9000) were initiated with 0, 25, 50, 100, 175 o r 250 p.p.b. AFB(1) by a 30 min immersion. Experimental diets containing 0, 250, 500, 750, 1000 or 1250 p.p.m. I3C were administered starting at 3 mon ths and fish were sampled for liver tumors at 11-13 months. Promotion at th e level of tumor incidence was statistically significant for all dietary le vels, except 250 p.p.m. Relative potency for promotion markedly increased a t dietary levels >750 p.p.m. We propose that more than one mechanism could be involved in promotion and that both estrogenic and Ah receptor-mediated pathways could be active. The estrogenicity of I3C, measured as its ability to induce vitellogenin tan estrogen biomarker in oviparous vertebrates) wa s evident at the lowest dietary level (250 p.p.m.), whereas CYP1A (a P450 i sozyme induced through the Ah receptor pathway) was not induced until dieta ry levels of 1000 p.p.m. Therefore, at lower dietary levels, promotion by I 3C in this model could be explained by estrogenic activities of I3C acid de rivatives, as it is known that estrogens promote hepatocarcinogenesis in tr out. Much stronger promotion was observed at high dietary I3C levels (1000 and 1250 p.p.m.), at which levels both CYP1A and vitellogenin were induced.