Atorvastatin and its metabolites differentially modulate the interaction of PXR with co-regulators. (A–C) HepG2 cells were co-transfected with expression plasmids encoding GAL4-DBD/co-activator-RID fusion proteins, as indicated, and an expression plasmid encoding VP16-AD/PXR-LBD (108–434) fusion protein (+) or empty expression vector pVP16-AD (–). Columns show the mean fold induction (±SD) of the normalized activity of co-transfected pGL3-G5 after 40 h of treatment with 0.1% DMSO, 30 µM atorvastatin (ATV), 30 µM atorvastatin lactone, (ATV-L), 30 µM ortho-hydroxy atorvastatin(o-OH-ATV), 30 µM para-hydroxy atorvastatin (p-OH-ATV) and 10 µM rifampin (RIF). The activity of cells transfected with the respective expression plasmid combination and treated with DMSO only, was designated as 1. (D) HepG2-PXR cells were co-transfected with plasmids encoding GAL4-DBD/SMRT-RID fusion protein and VP16-AD/PXR-LBD (108–434) fusion protein (+) or empty expression vector pVP16-AD (–). Columns show the means (±SD) of normalized pGL3-G5 reporter activity after 24 h of treatment with compounds, as described above. Data were analysed by two-way anova with Bonferroni's post-test. ***P < 0.001, *P < 0.05, significantly different from corresponding value with empty expression vector (–).