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Vol. 29, Issue 11, 1499-1504, November 2001
Molecular Toxicology, School of Biomedical and Life Sciences,
University of Surrey, Guildford, Surrey, United Kingdom (W.E.-S.,
G.G.G, N.P.); and Drug Metabolism and Pharmacokinetics,
GlaxoSmithKline, the Frythe, Welwyn, Herts, United Kingdom (A.A.)
Regulation of the CYP3A4 gene has been studied using an in vitro
reporter gene assay. The effect of 17 xenobiotics on ~1
kilobase of the CYP3A4 proximal promoter, upstream of a
secretory placental alkaline phosphatase reporter gene was investigated
following transfection into the HepG2 cell line. Transfections were
carried out either in the basal system or with cotransfection of
expression plasmids for the human pregnane X receptor (hPXR) and the
human glucocorticoid receptor (hGR), two important receptors in the regulation of CYP3A4 gene expression. Compounds were tested at four
concentrations, and the resulting data were used to calculate maximal
induction (Imax) and EC50
values. An "overall inductive ability" (IA) was derived by dividing
Imax by EC50. Of the compounds tested seven were established transcriptional inducers, all of which
were positive in the in vitro assay. The remaining 10 compounds represented a group with preliminary evidence for CYP3A transcriptional activation. Nine of these compounds produced statistically significant inductions in vitro, with only pravastatin failing to activate the
reporter gene. This is of potential interest in light of the high IA
values observed with the other structurally and functionally similar
statins tested. We conclude that a four-concentration-point, in vitro
model is capable of identifying CYP3A4 transcriptional inducers and
yields an IA value allowing the ranking of compounds for their overall
ability to induce CYP3A4 transcription. In addition, the majority of
the compounds tested showed increased IA values in the hPXR/hGR
cotransfected system, underpinning the importance of these receptors in
CYP3A4 gene transcriptional regulation.
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