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Modulation of Hormonal Induction of Tyrosine Aminotransferase and Glucocorticoid Receptors by Aflatoxin B₁ and Sterigmatocystin in Reuber Hepatoma Cells¹

Department of Toxicology and Microbial Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya, Tokyo 162, Japan

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.

¹ This investigation was partly supported by Grant-in-Aids for Cancer and Biotoxin Researches from the Ministry of Education, Science and Culture, Japan, and for Monoclonal Antibody from the Japan Private School Promotion Foundation, Tokyo.

² To whom requests for reprints should be addressed.

Received 4/ 9/87. Revised 4/20/88. Accepted 6/16/88.