Runge-Morris M, Rose K, Kocarek T A
Institute of Chemical Toxicology, Wayne State University, Detroit, MI 48201, USA.
Drug Metab Dispos. 1996 Oct;24(10):1095-101.
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.
由于激素与硫酸转移酶多基因家族的分子调控有关，因此在体内和原代大鼠肝细胞培养中研究了糖皮质激素和抗糖皮质激素对大鼠肝脏羟类固醇硫酸转移酶-a和芳基硫酸转移酶IV基因表达的影响。成年雄性Sprague-Dawley大鼠连续三天用2%吐温-20载体、或100mg/kg地塞米松、倍他米松、氢化可的松或曲安奈德处理。倍他米松和曲安奈德显著增加肝脏芳基硫酸转移酶IV mRNA水平，分别约为对照的252%和约452%。地塞米松显著增加羟类固醇硫酸转移酶-a mRNA和蛋白水平，分别约为对照的150%和约316%。相反，用羟类固醇硫酸转移酶-a底物脱氢表雄酮进行体内处理显著降低羟类固醇硫酸转移酶-a mRNA水平（相对于对照降低约55%）。为了确定糖皮质激素介导的硫酸转移酶表达变化是否是由于对肝细胞的直接作用所致，在原代大鼠肝细胞培养中进行了研究。曲安奈德和倍他米松增加了肝细胞培养物中硫酸转移酶mRNA表达，而氢化可的松被证明是一种效果较差的诱导剂。将糖皮质激素对硫酸转移酶基因表达的影响与糖皮质激素对酪氨酸转氨酶表达的影响进行了比较，酪氨酸转氨酶是一种已知受经典糖皮质激素受体介导机制调控的基因。当地塞米松以10(-7)M的浓度添加到培养基中时，其对芳基硫酸转移酶IV和酪氨酸转氨酶mRNA水平产生最大增加，而羟类固醇硫酸转移酶-a mRNA水平在10(-5)M的地塞米松浓度下持续增加。用抗糖皮质激素RU-486（10(-5)M）处理肝细胞分别抑制地塞米松刺激的芳基硫酸转移酶和酪氨酸氨基转移酶mRNA表达约48%和约35%，但对羟类固醇硫酸转移酶mRNA表达的影响较小。这些结果表明，糖皮质激素分别通过经典的糖皮质激素受体介导机制和非经典机制调节大鼠肝脏芳基硫酸转移酶IV和羟类固醇硫酸转移酶-a。
