PT  - JOURNAL ARTICLE
AU  - Melissa Runge-Morris
AU  - Wei Wu
AU  - Thomas A. Kocarek
TI  - Regulation of Rat Hepatic Hydroxysteroid Sulfotransferase (SULT2-40/41) Gene Expression by Glucocorticoids: Evidence for a Dual Mechanism of Transcriptional Control
AID  - 10.1124/mol.56.6.1198
DP  - 1999 Dec 01
TA  - Molecular Pharmacology
PG  - 1198--1206
VI  - 56
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/56/6/1198.short
4100  - http://molpharm.aspetjournals.org/content/56/6/1198.full
SO  - Mol Pharmacol1999 Dec 01; 56
AB  - Glucocorticoid-inducible hydroxysteroid sulfotransferase (SULT2-40/41) gene transcription was investigated in primary cultured rat hepatocytes transiently transfected with a series of SULT2-40/41 5′-flanking region-luciferase reporter constructs, with emphasis on examining the functional role of an inverted repeat-0 nuclear receptor motif (IR0). Treatment of transfected cultures with any of four glucocorticoids activated luciferase expression from a construct containing 1938 base pairs (bp) of the SULT2-40/41 gene 5′-flanking sequence, whereas deletion of bp −227 to −158 (containing the IR0 motif) largely abolished the effect. On closer analysis, treatment of hepatocyte cultures with either of the potent glucocorticoids dexamethasone [strong cytochrome P-450 3A (CYP3A) inducer] or triamcinolone acetonide (weak CYP3A inducer) produced dose-dependent increases in luciferase activity when hepatocytes were transiently transfected with a construct containing as little as 158 bp of 5′-flanking sequence or containing a mutated IR0 motif. The dexamethasone dose-dependent increase in luciferase activity continued through a dose of 10−6 M when the transfected construct contained the IR0 motif, but was maximal at 10−7 M when the transfected construct lacked the IR0 motif. In contrast, triamcinolone acetonide-induced luciferase activity was maximal at a dose of 10−7 M, irrespective of the presence or absence of the IR0 motif. Coincubation of transfected hepatocytes with 10−8 M dexamethasone and the antiglucocorticoid RU486 inhibited luciferase expression. Luciferase induction by the prototypical CYP3A inducer pregnenolone 16α-carbonitrile was restricted to constructs containing the IR0 motif. These data suggest that glucocorticoid-inducible SULT2-40/41 gene expression occurs through a dual mechanism, whose components possibly involve the glucocorticoid receptor and the pregnane X receptor.