Induction of cytochrome P450 3A by paclitaxel in mice: pivotal role of the nuclear xenobiotic receptor, pregnane X receptor.
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 alpha-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 EC(50) of 5.6 and 0.27 microM, 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 V(max) of testosterone 6 beta-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.
Nallani
Srikanth C
SC
Division of Pharmaceutical Sciences, College of Pharmacy and the Department of Molecular and Cellular Physiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0004, USA.
Goodwin
Bryan
B
Maglich
Jodi M
JM
Buckley
Donna J
DJ
Buckley
Arthur R
AR
Desai
Pankaj B
PB
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A; D004790:Enzyme Induction; D066298:In Vitro Techniques; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D001189:Aryl Hydrocarbon Hydroxylases; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017239:Paclitaxel