PT  - JOURNAL ARTICLE
AU  - Srikanth C. Nallani
AU  - Bryan Goodwin
AU  - Jodi M. Maglich
AU  - Donna J. Buckley
AU  - Arthur R. Buckley
AU  - Pankaj B. Desai
TI  - Induction of Cytochrome P450 3A by Paclitaxel in Mice: Pivotal Role of the Nuclear Xenobiotic Receptor, Pregnane X Receptor
AID  - 10.1124/dmd.31.5.681
DP  - 2003 May 01
TA  - Drug Metabolism and Disposition
PG  - 681--684
VI  - 31
IP  - 5
4099  - http://dmd.aspetjournals.org/content/31/5/681.short
4100  - http://dmd.aspetjournals.org/content/31/5/681.full
SO  - Drug Metab Dispos2003 May 01; 31
AB  - 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 ofCYP3A in different species. We investigated the role of PXR activation, in vitro and in vivo, in mediating Cyp3ainduction by paclitaxel. Pregnenolone 16α-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 6β-hydroxylation in microsomal fraction increased 15- and 30-fold in paclitaxel- and PCN-treated mice, respectively. TheCyp3a 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. The American Society for Pharmacology and Experimental Therapeutics