Inhibition of Hepatocarcinogenesis by Adrenocorticotropin in Aflatoxin B1-Treated Rats2

Abstract

We examined whether hormones would modify the carcinogenic action of aflatoxin B₁ (AFB₁). Four groups of inbred Fischer rats received AFB₁, 125 µg per animal, weekly per os. In three of the groups, certain hormones were administered simultaneously: One group received 1 U growth hormone (GH) sc weekly, another was given 4 U adrenocorticotropin (ACTH) weekly, and a third received 0.5 U insulin weekly sc. AFB₁, ACTH, and insulin were given for 20 weeks; GH was given for only 10 weeks. The control group did not receive hormone adjuvant. In each group, 4 animals were killed at 7, 14, 21, 28, and 35 weeks; the remaining rats were killed at 77 weeks. Their livers were carefully examined and samples prepared for light and electron microscopy. Animals receiving AFB₁ and ACTH failed to exhibit hepatocellular carcinoma. On the other hand, malignant lymphoma appeared at 56 weeks in 3 of the 6 surviving males on this regime. AFB₁, alone or when given with insulin or GH, caused hepatocellular carcinoma in all animals; in these, lymphoma was not observed. Lymphoma comprised two cell types, each with similar nuclear characteristics but differing in their nucleocytoplasmic ratios and in the amount and distribution of cytoplasmic organelles. Alterations leading to hepatocellular carcinoma were examined at various stages of development. “Basophilic hyperplasia” reflected an increase in free ribosomes. “Hyperplastic nodules” were composed of hepatocyte aggregates with characteristics similar to those encountered in the earlier stage. Both the “neoplastic nodules” and hepatocellular carcinomas were formed by cells containing large, “smooth fingerprints” and free ribosomal aggregates. These features supported the concept that AFB₁ impairs ribosomal binding to endoplasmic reticulum membranes. The failure of ACTH-treated animals to develop hepatocellular carcinoma was ascribed to the effect of adrenal cortical stimulation upon membrane-polysome binding.