Abstract

Because hormones have been implicated in the molecular regulation of the sulfotransferase multigene family, the effects of glucocorticoid and antiglucocorticoid hormones on rat hepatic hydroxysteroid sulfotransferase-a and aryl sulfotransferase IV gene expression were investigated in vivo and in primary rat hepatocyte culture. Adult male Sprague-Dawley rats were treated for three consecutive days with 2% Tween-20 vehicle, or 100 mg/kg of dexamethasone, betamethasone, hydrocortisone, or triamcinolone acetonide. Betamethasone and triamcinolone acetonide significantly increased hepatic aryl sulfotransferase IV mRNA to levels that were approximately 252% and approximately 452% of control, respectively. Dexamethasone significantly increased hydroxysteroid sulfotransferase-a mRNA and protein to levels that were approximately 150% and approximately 316% of control, respectively. In contrast, in vivo treatment with hydroxysteroid sulfotransferase-a substrate dehydroepiandrosterone significantly decreased hydroxysteroid sulfotransferase-a mRNA levels (by approximately 55% relative to control). To determine if glucocorticoid mediated changes in sulfotransferase expression occurred as a result of direct effects on the hepatocyte, studies were performed in primary rat hepatocyte culture. Triamcinolone acetonide and betamethasone increased sulfotransferase mRNA expression in hepatocyte culture and hydrocortisone proved to be a less effective inducer. Effects of glucocorticoids on sulfotransferase gene expression were compared with glucocorticoid effects on tyrosine aminotransferase expression, a gene known to be regulated by a classical glucocorticoid receptor-mediated mechanism. Dexamethasone produced maximal increases in aryl sulfotransferase IV and tyrosine aminotransferase mRNA levels when added to culture medium at a concentration of 10(-7) M, whereas hydroxysteroid sulfotransferase-a mRNA levels continued to increase through a dexamethasone concentration of 10(-5) M. Treatment of hepatocytes with the antiglucocorticoid RU-486 (10(-5) M) inhibited dexamethasone-stimulated aryl sulfotransferase and tyrosine amino-transferase mRNA expression by approximately 48% and approximately 35%, respectively, but had less effect on hydroxysteroid sulfotransferase mRNA expression. These results suggest that glucocorticoids regulate rat hepatic aryl sulfotransferase IV and hydroxysteroid sulfotransferase-a via classical glucocorticoid receptor-mediated and non-classical mechanisms, respectively.