The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339

Cytochrome P-450 3A4 (CYP3A4), the predominant cyto-chrome P-450 expressed in adult human liver, is subject to transcriptional induction by a variety of structurally unrelated xenobiotics, including the antibiotic rifampicin. The molecular mechanisms underlying this phenomenon are poorly under-stood. We transfected a human liver-derived cell line (HepG2) with various CYP3A4-luciferase reporter gene constructs con-taining a nested set of 59-deletions of the CYP3A4 59-flanking region. Rifampicin-inducible transcription of the reporter gene was observed only with the longest construct, which encom-passed bases 213000 to 153 of CYP3A4 (3-fold induction). The responsive region was functional regardless of its position or orientation relative to the proximal promoter of CYP3A4 and was capable of conferring rifampicin-inducible expression on