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 cytotoxicity 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 micrograms/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 micrograms/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.