Identification of novel pregnane X receptor activators from traditional Chinese medicines
Graphical abstract
Introduction
Herbal remedies including traditional Chinese medicines (TCMs), Japanese and Indian medicines are gaining more and more popularity in the world, which gives an alternate choice to treat all kinds of diseases. Herbal medicines are believed to be natural and therefore safe by many patients. However, frequent and indiscriminate use of herbal products has been associated with adverse effects including interactions with therapeutic drugs (Fugh-Berman, 2000, Izzo and Ernst, 2009). For example, a number of clinical reports indicate pharmacokinetic interactions between St. John's wort and prescribed medications such as immunosuppressants (Bauer et al., 2003), contraceptives (Pfrunder et al., 2003) and antiretroviral drugs (Piscitelli et al., 2000). Some of these interactions were found to be attributed to the inducing effect of St. John's wort on hepatic and intestinal CYP3A4 (Dürr et al., 2000, Moore et al., 2000).
Many herbal medicines are known to up-regulate the expression of CYP3A4, however, the molecular mechanisms by which these herbs induce CYP3A4 have remained largely unclear. The discovery of pregnane X receptor (PXR) gives insight into the signalling mechanism of CYP3A4 induction (Bertilsson et al., 1998, Lehmann et al., 1998). It is a ligand-activated transcription factor that plays a key role in the regulation of CYP3A4 (Kliewer et al., 2002). Upon binding to a ligand, the activated PXR forms a heterodimer with retinoid X receptor, recruits cofactors, and binds to the promoter region of CYP3A4 gene, resulting in increased CYP3A4 transcription (Willson and Kliewer, 2002). Therefore, caution should be taken when PXR activators were administered with prescribed medications metabolized by CYP3A4 at the same time.
Human PXR activators include a variety of structurally diverse compounds such as prescribed drugs (Drocourt et al., 2001), herbal constituents (Watkins et al., 2003), endogenous hormones (Kliewer et al., 1998) and environmental pollutants (Coumoul et al., 2002). Herbal medicines demonstrated to trans-activate PXR include licorice (Mu et al., 2006), gugulipid (Brobst et al., 2004), Schisandra chinensis (Mu et al., 2006), Ginkgo biloba (Yeung et al., 2008) and St. John's wort (Moore et al., 2000). Furthermore some herbal ingredients have been identified as PXR activators such as hyperforin (Wentworth et al., 2000), taxol (Harmsen et al., 2009), artemisinin (Burk et al., 2005), guggulsterone (Brobst et al., 2004), schisandrol B, schisandrins A and B (Mu et al., 2006).
In our previous work, Danshen ethanol extract was found to activate PXR and its active components tanshinone IIA and cryptotanshinone were characterized as PXR activators (Yu et al., 2009). The aim of the present study was to investigate whether other commonly used TCMs and their bioactive compounds could activate PXR signalling pathway and thus have the potential to induce the expression of CYP3A4.
Section snippets
Materials
Moloney murine leukemia virus (M-MuLV) reverse transcriptase was obtained from MBI Fermentas (Hanover, MD). Dual-luciferase reporter assay system and pRL-TK vector were provided by Promega (Madison, WI). Plasmid miniprep kit was purchased from Qiagen (Hilden, Germany). Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum, minimal essential medium (MEM) non-essential amino acids and lipofectamine 2000 were ordered from Invitrogen (Carlsbad, CA).
Ginkgo biloba and Isatis indigotica were
Activation of human PXR by ethanol extracts of TCMs
The tested 28 TCMs are most frequently used in China and likely to be taken with prescribed drugs. Reporter gene assays were performed to evaluate the trans-activation profile of human PXR by the ethanol extracts of these TCMs. As presented in Table 1, Ginkgo biloba, Ligusticum chuanxiong, Chinese angelica, prepared Rehmannia root, Epimedium brevicornum, Atractylodes macrocephala, Schisandra chinensis, Paeonia lactiflora, Ophiopogon japonicus, Polygonum multiflorum, Coptis chinensis, Artemisia
Discussion
A number of studies have been conducted to investigate the effect of individual compounds especially synthetic drugs on PXR activity, however, much less is known as to which herbal remedy is able to trans-activate this receptor. In the present study, twenty-eight commonly used TCMs were examined for their capability to activate PXR signalling pathway using an in vitro cell-based reporter gene assay. Our data showed that twenty-two of them could activate PXR and induce the CYP3A4 reporter gene,
Conclusion
In summary, we employed a reporter gene assay to evaluate the role of 28 TCMs and 34 bioactive components from these TCMs on trans-activation of human PXR. Our findings showed that 22 of these TCMs and 8 of their bioactive compounds could activate PXR signalling pathway and induce the CYP3A4 reporter gene. Therefore, these TCMs and constituents should be used with caution by patients to avoid unwanted herb–drug interactions. Nevertheless, there are several limitations in the present study. For
Acknowledgements
This work was supported by National Major Special Project for Science and Technology Development of Ministry of Science and Technology of China (2009ZX09304-003) (S. Zeng) and National Natural Science Foundation of China (81001475) (C.N. Yu).
References (28)
- et al.
PXR-dependent induction of human CYP3A4 gene expression by organochlorine pesticides
Biochemical Pharmacology
(2002) Herb–drug interactions
Lancet
(2000)- et al.
An orphan nuclear receptor activated by pregnanes defines a novel steroid signalling pathway
Cell
(1998) - et al.
Development of high-performance liquid chromatographic fingerprints for distinguishing Chinese Angelica from related umbelliferae herbs
Journal of Chromatography A
(2005) - et al.
Indinavir concentrations and St John's wort
Lancet
(2000) - et al.
The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF)
Journal of Ethnopharmacology
(1996) - et al.
PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA
Chemico-Biological Interactions
(2009) - et al.
Evaluation of the protective effects of Schisandra chinensis on Phase I drug metabolism using a CCl4 intoxication model
Journal of Ethnopharmacology
(1999) - et al.
Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients
British Journal of Clinical Pharmacology
(2003) - et al.
Identification of a human nuclear receptor defines a new signalling pathway for CYP3A induction
Proceedings of the National Academy of Sciences of the United States of America
(1998)
Guggulsterone activates multiple nuclear receptors and induces CYP3A gene expression through the pregnane X receptor
Journal of Pharmacology and Experimental Therapeutics
Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor
Molecular Pharmacology
Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2 C in human hepatocytes
Drug Metabolism and Disposition
St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4
Clinical Pharmacology & Therapeutics
Cited by (72)
Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine
2023, Acta Pharmaceutica Sinica BPharmacokinetic herb-disease-drug interactions: Effect of ginkgo biloba extract on the pharmacokinetics of pitavastatin, a substrate of Oatp1b2, in rats with non-alcoholic fatty liver disease
2021, Journal of EthnopharmacologyCitation Excerpt :The PXR pathway could be a potential mechanism for EGB to regulate hepatic lipid metabolism, bile acid homeostasis, and insulin resistance in NAFLD rats, consistent with literature reports. In the literature, EGB and its terpene lactones have been reported as PXR activators in different studies (Li et al., 2009; Yu et al., 2011; Ye et al., 2016). EGB and its flavonoid ingredients can also lessen liver lipid accumulation by up-regulating the rate-limiting enzyme carnitine palmitoyltransferase (CPT)-1A in the β-oxidation of long-chain fatty acids (Wei et al., 2014), which may be another mechanism of EGB.
Potential cytochrome P450-mediated pharmacokinetic interactions between herbs, food, and dietary supplements and cancer treatments
2021, Critical Reviews in Oncology/HematologyEffects of Shengmai San on key enzymes involved in hepatic and intestinal drug metabolism in rats
2021, Journal of Ethnopharmacology
- 1
Equal contribution to this paper.