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Dose-dependent reduction of N-2-fluorenylacetamide-induced liver cancer and enhancement of bladder cancer in rats by butylated hydroxytoluene.

The modifying effect of four dose levels of butylated hydroxytoluene (BHT) on liver and bladder carcinogenesis by N-2-fluorenylacetamide (FAA) was studied in rats. FAA (200 ppm) was fed simultaneously with four levels of BHT (300, 1000, 3000, and 6000 ppm) to male F344 Fischer strain rats. Groups of animals were killed at 6, 12, 18, and 25 weeks. Hepatocellular-altered foci in the liver were identified histochemically by the exclusion of cellular iron after iron loading and by reaction for gamma-glutamyltranspeptidase. FAA alone induced altered hepatocellular foci which increased in number with duration of exposure, and by 25 weeks of feeding, 100% of rats had liver neoplasms. Concurrent feeding of BHT produced a dose-dependent reduction in the numbers of altered foci and the areas of liver sections occupied by histochemically altered cells, as well as a reduction in the incidence of liver neoplasms and the number of neoplasms per animal. These findings indicate that reduction of the number of foci at an early stage is predictive of reduced incidence of neoplasms at a late stage. Thus, BHT inhibited in a dose-dependent manner the hepatocarcinogenesis of concurrently fed FAA. However, although no bladder neoplasms occurred in rats given either BHT or FAA alone, groups fed BHT and FAA together developed bladder neoplasms in proportion to the dose of BHT. The effect of BHT on both liver and bladder carcinogenesis could be explained by BHT causing an alteration of the metabolism of FAA in the liver, resulting in less activation and greater urinary excretion of carcinogenic metabolites. In addition, BHT at high dose levels may exert a promoting effect on bladder carcinogenesis. Accordingly, it is suggested that the chemopreventive effect of phenolic antioxidants should be investigated with attention to the possibility that they not only inhibit carcinogenesis in the main target organs but also modify carcinogenesis in other organs.