EFFECTS OF CHRONIC ADMINISTRATION OF LOW-DOSES OF 2-AMINO-3,8-DIMETHYLIMIDAZO-[4,5-F]QUINOXALINE ON GLUTATHIONE-S-TRANSFERASE PLACENTAL FORM-POSITIVE FOCI DEVELOPMENT IN THE LIVERS OF RATS FED A CHOLINE-DEFICIENT DIET

Effects of chronic administration of 2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx) at the very low doses of 0.4 and 4 ppm, respectiv ely 1000- and 100-fold less than the dose shown to be carcinogenic (40 0 ppm), on the liver of rats fed a choline-deficient (CD) diet were ex amined in terms of glutathione S-transferase placental form (GST-P)-po sitive foci. Male F344 rats were given CD diet containing 0, 0.4 or 4 ppm MeIQx for 20 or 40 weeks. As controls, rats received choline-suppl emented (CS) diet in the same manner. MeIQx at 4 ppm in the CD diet si gnificantly increased both the number and area of GST-P-positive foci, the values being 2.3- and 2.1-fold at 20 weeks and 2.0- and 3.3-fold at 40 weeks, respectively, compared with those observed for CD diet al one. MeIQx at 0.4 ppm in CD diet did not affect the development of GST -P-positive foci. No influence of the heterocyclic amine was found in the CS groups, where only very small numbers of minute lesions were ob served. The level of MeIQx-DNA adducts in rats given the CD diet conta ining 4 ppm MeIQx was 2- to 3-fold lower than that in rats given the C S diet containing 4 ppm MeIQx at 20 and 40 weeks. This result indicate s that DNA adduct formation and cell proliferation are both required f or the increase of GST-P-positive foci in rats fed 4 ppm MeIQx in a CD diet. The above findings strongly suggest that MeIQx could be carcino genic even at 4 ppm under CD conditions, where liver cell regeneration is continuously occurring.