LACK OF TUMOR-PROMOTING EFFECTS OF FLAVONOIDS - STUDIES ON RAT-LIVER PRENEOPLASTIC FOCI AND ON IN-VIVO AND IN-VITRO GAP JUNCTIONAL INTERCELLULAR COMMUNICATION

Possible tumor-promoting activity of four flavonoids, quercetin (QC), tangeretin (TG), flavone (FO), and flavanone (FN), was examined in a r at liver short-term carcinogenesis assay as,yell as with in vivo and i n vitro assays of inhibition of gap junctional intercellular communica tion (GJIC). Rat hepatocarcinogenesis was induced by aflatoxin B-1 tre atment followed by a selection phase (2-acetylaminofluorene treatment and partial hepatectomy), then treatment with or without test chemical s (in vivo studies of antipromotion were not performed). Using glutath ione S-transferase placental form (GST-P)-positive foci, we compared t he effects of flavonoids (at 1,000 ppm in the diet) with the effects o f phenobarbital (PB) on the occurrence of liver preneoplastic lesions. In addition, we studied the effects of flavonoids on GJIC in the live rs derived from these experiments and in two types of cultured cells. No significant difference in the number and area of GST-P-positive foc i was found after one or three months of treatment between any flavono id group and control group. In the positive control group, PB markedly increased the numbers and areas of preneoplastic lesions at three mon ths. Whereas PB also decreased by 60% the average size of lucifer yell ow dye spread in slices of liver parenchyma free of preneoplastic lesi ons among the different flavonoids;, only TG decreased the dye transfe r in vivo: by 30% at one month and 50% at three months. With the dye t ransfer assay applied to a rat liver. epithelial cell line (REL) and t he Chinese hamster V79 metabolic cooperation assay, none of the tested flavonoids (less than or equal to 25 mu M) inhibited GJIC. Conversely , protective properties were seen for some of the compounds in antipro motion in vitro studies, because TG and FN enhanced the dye transfer i n REL cells and FO, TG, and QC partly prevented the inhibition of meta bolic cooperation by 12-O-tetradecanoylphorbol-13-acetate. Thus, taken together, our results suggest that QC, FO, and FN do not show tumor-p romoting activity. Concerning TG, some discrepancies in the in vivo da ta are observed. Some of them (GJIC inhibition in liver slices) are pr obably more relevant to promotion of hepatocarcinogenesis.