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Vol. 31, Issue 5, 681-684, May 2003
Division of Pharmaceutical Sciences, College of Pharmacy and the
Department of Molecular and Cellular Physiology, University of
Cincinnati Medical Center, Cincinnati, Ohio (S.C.N., D.J.B., A.R.B.,
P.B.D.); and Nuclear Receptor Discovery Research, GlaxoSmithKline Inc.,
Research Triangle Park, North Carolina (B.G., J.M.M.)
Paclitaxel, a taxane anti-microtubule agent, is known to
induce CYP3A in rat and human hepatocytes. Recent
studies suggest that a member of the nuclear receptor family, pregnane
X Receptor (PXR), is a key regulator of the expression of
CYP3A in different species. We investigated the role of
PXR activation, in vitro and in vivo, in mediating Cyp3a
induction by paclitaxel. Pregnenolone 16
-carbonitrile (PCN), an
antiglucocorticoid, was employed as a positive control for mouse PXR
(mPXR) activation in vitro, and Cyp3a induction in vivo.
In cell based reporter gene assays paclitaxel and PCN activated mPXR
with an EC50 of 5.6 and 0.27 µM, respectively. Employing
PXR wild-type and transgenic mice lacking functional PXR (
/), we
evaluated the expression and activity of CYP3A following treatment with
paclitaxel and PCN. Paclitaxel significantly induced CYP3A11 mRNA and
immunoreactive CYP3A protein in PXR wild-type mice. Consistent with
kinetics of CYP3A induction, the Vmax of testosterone 6
-hydroxylation in microsomal fraction increased 15- and 30-fold in paclitaxel- and PCN-treated mice, respectively. The
Cyp3a induction response was completely abolished in
paclitaxel- and PCN-treated PXR-null mice. This suggests that
paclitaxel-mediated CYP3A induction in vivo requires an intact
PXR-signaling mechanism. Our study validates the use of PXR activation
assays in screening newer taxanes for potential drug interactions that
may be related to PXR-target gene induction.
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