Effects of liver X receptor agonists on human pregnane X receptor activity and CYP3A4 expression

Abstract

We previously reported that the prototypical liver X receptor (LXR) agonists, 24(S),25-epoxycholesterol, an endogenous oxysterol, and T0901317, a synthetic ligand, also induce rodent CYP3A expression in primary cultured hepatocytes as a consequence of pregnane X receptor (PXR) activation, albeit at somewhat higher concentrations than are necessary to activate LXR. In this study, we examined the effects of these two agents on CYP3A4 mRNA content in primary cultured human hepatocytes and on human PXR activity, using a transactivation assay in HepG2 cells. Treatment of primary cultured human hepatocytes with 1 μM or 10 nM T0901317 increased CYP3A4 content ~50-fold (n=3 preparations) or ~10-fold (n=2 preparations), respectively. By comparison, treatment with 10 or 30 μM 24(S),25-epoxycholesterol did not increase CYP3A4 mRNA content more than ~2-fold in any preparation. T0901317 potently activated PXR-responsive reporter expression with an EC50 of ~17 nM, and the maximal increase produced at 1 μM T0901317 (31-fold) was approximately the same as that produced by treatment with 50 μM rifampicin (28-fold). Treatment with 24(S),25-epoxycholesterol at concentrations up to 30 μM had no effect on PXR activity. These results demonstrate that T0901317 is a potent human PXR activator and CYP3A4 inducer, while 24(S),25-epoxycholesterol is inactive in this regard. Supported by HL50710 and ES06636.