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 EC 50 of 2 and 1.25 M 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.

Effects of Short-Term and Long-Term Pretreatment of Schisandra Lignans on Regulating Hepatic and Intestinal CYP3A in Rats

“…It was interesting to note that both aqueous and ethanolic extracts of Schisandra chinensis Baill up-regulated CYP3A expression through PXR activation (Mu et al, 2006). However, the in vivo CYP3A-inducing potency of SLE had not been previously confirmed.…”

“…SLE has also been found to be capable of increasing the oral bioavailability of tacrolimus, a substrate of both CYP3A and P-glycoprotein, in healthy volunteers (Xin et al, 2007). Interestingly, it was found that SLE treatment in hepatocytes induced both CYP3A and CYP2C expression through activating orphan nuclear receptor pregnane X receptor (PXR) (Mu et al, 2006). Thus, it is reasonable to propose that SLE may exert a biphasic effect on regulating CYP3A expression and activity, i.e., short-term inhibition and long-term induction, the same as that observed from St. John's wort (Rengelshausen et al, 2005;Xie and Kim, 2005).…”

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

“…However, PXR and CAR were also shown to contribute to the overall UGT1A1 response to flavonoids [70]. ↑ luciferase activity ↑ CAT activity for α and γ Effective binding to PXR ↑ CYP3A4, no effect on UGT1A1 or MDR-1 ↑ MDR-1, ↑ UGT1A1, no effect on CYP3A4 ↑ CYP3A4/3A5 by γ Zhou et al [62] Landes et al [63] Zhou et al [62] Zhou et al [62] Zhou et al [62] Landes et al [63] Vitamin E CYP3A4 cell-based reporter assay with PXR α-, β-, γ-, and δ-tocopherols Ligand-binding assay PXR Mu et al [68] Abbreviations: AUC, area under the concentration-time curve; CAT, chloramphenicol acetyltransferase reporter gene activity; CYP, cytochrome P450; C max , maximum observed concentration; MDR, multidrug resistance gene; MRP, multidrug resistanceassociated protein; PXR, pregnane X receptor; t 1/2 , half-life; TCM, traditional Chinese medicine; UGT, uridine diphosphoglucuronosyl transferase.…”

“…Other studies using gene reporter assays or mRNA levels of CYP3A4 in human hepatocytes showed the potential of several CAMs to induce CYP3A4 by activation of PXR: Gugulipid, or its chemical constituents guggulsterones, derived from the Mukul myrrh tree [64][65][66][67], hops [64], two traditional Chinese medicines (TCMs), Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selective constituents [68], carotenoids, especially β-carotene, and retinol [69].…”

Pregnane X receptor and natural products: beyond drug–drug interactions

“…The primary hepatoprotective and immunomodulating constituents are the lignans, schisandrin, deoxyschisandrin, gomisins and pregomisin [101]. Recently, it was reported that wu wei zi extracts, as well as several compounds found in wu wei zi including Schisandrol B and Schisandrin A and B (Table 1), are potent and efficacious PXR agonists in reporter gene assays [57]. Moreover, they efficaciously induce the PXR target genes CYP3A4 and -2C9 in primary hepatocytes.…”