title: Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats.
abstract: The traditional Chinese medicines (TCMs) are essential components of alternative medicines. Many TCMs are known to alter the expression of hepatic drug-metabolizing enzymes and transporters. The molecular mechanism by which TCMs and/or their constituents regulate enzyme and transporter expression, however, has remained largely unknown. In this report, we show that two TCMs, Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selected constituents activate the xenobiotic orphan nuclear receptor pregnane X receptor (PXR). Treatment with TCM extracts and the Schisandrol and Schisandrin constituents of Wu Wei Zi induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays and in primary hepatocyte cultures. The affected enzymes and transporters include CYP3A and 2C isozymes and the multidrug resistance-associated protein 2. In transient transfection and reporter gene assays, the Schisandrin constituents of Wu Wei Zi had an estimated EC50 of 2 and 1.25 microM on hPXR and mPXR, respectively. Interestingly, mutations that were intended to alter the pore of the ligand-binding cavity of PXR had species-specific effects on the activities of the individual Schisandrols and Schisandrins. In rats, the administration of Wu Wei Zi and Gan Cao increased the metabolism of the coadministered warfarin, reinforcing concerns involving the safe use of herbal medicines and other nutraceuticals to avoid PXR-mediated drug-drug interactions. Meanwhile, the activation of PXR and induction of detoxifying enzymes provide a molecular mechanism for the hepatoprotective effects of certain TCMs.
authors.affiliation: Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mu
authors.forename: Jinnan
authors.initials: J
authors.lastname: Zhang
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: Toma
authors.forename: Songrong
authors.initials: S
authors.lastname: Ren
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
authors.forename: Maria
authors.initials: M
authors.lastname: Yaramus
authors.forename: Andrew
authors.initials: A
authors.lastname: Baum
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D029882:Glycyrrhiza uralensis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008516:Medicine, Chinese Traditional; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011987:Receptors, Steroid / Q000187:drug effects*; D032141:Schisandra; D013045:Species Specificity; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D010936:Plant Extracts; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014859:Warfarin