Regulation of human hepatic hydroxysteroid sulfotransferase (SULT2A1) expression by rifampicin.

Abstract

Human hydroxysteroid sulfotransferase (SULT2A1) catalyzes the sulfonation and detoxication of endogenous and xenobiotic substrates. The effects of rifampicin (RIF), a ligand of the human pregnane X receptor (PXR), on SULT2A1 expression were evaluated in primary cultured human hepatocytes. SULT2A1 mRNA content was increased by RIF treatment in seven hepatocyte preparations, but was reduced in three others. Transient transfection of HepG2 cells with reporter constructs localized two RIF-responsive regions in the SULT2A1 promoter (one at -6160 and another at −54), which contained hepatocyte nuclear factor 4α (HNF4α) binding sites, as confirmed by EMSA and ChIP. Co-transfection of HepG2 cells with PXR suppressed reporter expression from constructs containing the HNF4α sites, and suppression was augmented by rifampicin treatment. Transfection with a DNA binding-defective PXR mutant failed to ablate the suppressive effects of PXR and rifampicin. These results suggest that rifampicin-liganded PXR suppresses human hepatic SULT2A1 expression through a mechanism that involves interference with HNF4α, possibly through a protein-protein interaction. Supported by ES05823 (M.R.M.), HL50710 (T.A.K.) and ES06636.