Modulation of Hormonal Induction of Tyrosine Aminotransferase and Glucocorticoid Receptors by Aflatoxin B₁ and Sterigmatocystin in Reuber Hepatoma Cells

Employing Reuber rat hepatoma cells, H4-II-E, the effects of aflatoxin B₁ (AFB₁) and sterigmatocystin (STC), which exhibit a similar cytotoxity but a marked difference in hepatocarcinogenicity, on the hormonal induction of tyrosine aminotransferase (TAT), on glucocorticoid receptors, and on their nuclear acceptor sites were investigated. AFB₁ strongly inhibited hydrocortisone-inducible TAT activity. The IC₅₀ value was 0.2 μg/ml. AFB₁ also showed weak inhibitory effects on insulin- and dibutyryl cyclic AMP-inducible TAT activities. In contrast, the IC₅₀ of STC on hydrocortisone-inducible TAT activity was 3.5 μg/ml, about 10 times higher than that of AFB₁. Dibutyryl cyclic AMP- and insulin-inductions were not depressed by STC. AFB₁ inhibited the formation of cytosolic glucocorticoid receptor-hormone complexes (GRCs) but STC did not. Moreover, AFB₁, activated in vitro by the microsomal cytochrome P-450 system, interfered more markedly in the formation of cytosolic GRCs than STC did. Sucrose density gradient analysis of GRCs and Scatchard analysis revealed that AFB₁ and STC mainly impaired glucocorticoid receptors and GRC-acceptor sites, respectively. The present data suggest a marked difference between AFB₁ and STC with regard to the inhibition of hormonal induction of liver specific enzymes.