Effects of Chronic Administration of Low Doses of 2‐Ammo‐3,8‐dimethylimidazo‐[4,5‐f]qumoxaline 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,S‐f]quinoxaline (MeIQx) at the very low doses of 0.4 and 4 ppm, respectively 1000‐ and 100‐fold less than the dose shown to be carcinogenic (400 ppm), on the liver of rats fed a choline‐deficient (CD) diet were examined in terms of glutathione S‐transferase placental form (GST‐P)‐positive 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‐supplemented (CS) diet in the same manner. MeIQx at 4 ppm in the CD diet significantly 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 alone. 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 observed. The level of MeIQx‐DNA adducts in rats given the CD diet containing 4 ppm MeIQx was 2‐ to 3‐fold lower than that in rats given the CS diet containing 4 ppm MeIQx at 20 and 40 weeks. This result indicates that DNA adduct formation and cell proliferation are both required for 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 carcinogenic even at 4 ppm under CD conditions, where liver cell regeneration is continuously occurring.