toremifene and indole-3-carbinol

Indole-3-carbinol (I3C), a compound found in Brassica vegetables has been widely studied for its chemopreventive properties. I3C has been shown to block tumor initiation and promotion; however, it also acts as a tumor promoter. I3C and some of its acid condensation products, particularly 3,3'-diindolylmethane (I33'), have exhibited antiestrogenic properties. We report that I33' acts as an estrogen in the rainbow trout liver in vitro and in vivo by inducing vitellogenin (Vg), a well-characterized biomarker for estrogens. Precision-cut liver slices from male rainbow trout, Oncorhynchus mykiss, were incubated at 14 degrees C for 96 h in media containing I3C, I33', or a mixture of I3C acid condensation products (RXN) (0-250 microM). I33' and RXN increased Vg levels in rainbow trout liver slices by over 300- and 20-fold, respectively, vs vehicle. The efficacy of I33' induction of Vg was comparable to 17 beta-estradiol (E(2)) with 2500-fold less potency. I33' and E(2) cotreatment resulted in additive Vg induction. Tamoxifen completely inhibited I33'-induced Vg induction, suggesting that Vg induction by I33' is entirely through the estrogen receptor. In vivo, juvenile male rainbow trout were fed I3C, RXN (0-2000 mg/kg), or I33' (0-250 mg/kg) for 2 weeks. At 2000 mg/kg, I3C induced Vg by over 100,000-fold compared to controls, which was comparable to 5 mg/kg 17 beta-estradiol (the dose resulting in maximum induction). I33' was five times as potent as I3C with equal efficacy. The potency of RXN was only 5% of I3C. Again, I33' and E(2) cotreatment resulted in additive Vg induction. I33' may have accounted for Vg increases observed in trout fed I3C as it is present in liver after oral dosing at concentrations (70 microM) expected to maximally induce Vg. In trout, results in vitro and in vivo document that I33' is estrogenic, consistent with our hypothesis that I3C promotes liver cancer in trout by estrogenic pathways.

Topics: Adenosine Triphosphate; Animals; Carcinogens; Chromatography, High Pressure Liquid; Estradiol; Estrogen Antagonists; Estrogens; Female; In Vitro Techniques; Indoles; Liver; Male; Mass Spectrometry; Models, Animal; Oncorhynchus mykiss; Tamoxifen; Time Factors; Toremifene; Vitellogenins