Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Mechanism of Panax notoginseng saponins modulation of miR-214-3p/NR1I3 affecting the pharmacodynamics and pharmacokinetics of warfarin

  • Yuting Yang (Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University) ;
  • Zhenyu Zhai (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University) ;
  • Huiming Yao (Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University) ;
  • Ling He (Department of Gerontology, The Second Affiliated Hospital of Nanchang University) ;
  • Jun Shao (Department of Cardiac Surgery, The Second Affiliated Hospital of Nanchang University) ;
  • Zirong Xia (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University) ;
  • Juxiang Li (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University)
  • Received : 2024.04.01
  • Accepted : 2024.05.14
  • Published : 2024.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: With the prevalence of dietary supplements, the use of combinations of herbs and drugs is gradually increasing, together with the risk of drug interactions. In our clinical work, we unexpectedly found that the combination of Panax notoginseng and warfarin, which are herbs that activate blood circulation and remove blood stasis, showed antagonistic effects instead. The purpose of this study was to evaluate the drug interaction between Panax notoginseng saponins (PNS) and warfarin, the main active ingredient of Panax notoginseng, and to explore the interaction mechanism. Methods: The effects and mechanisms of PNS on the pharmacodynamics and pharmacokinetics of warfarin were explored mainly in Sprague-Dawley rats and HepG2 cells. Elisa was used to detect the concentrations of coagulation factors, HPLC-MS to detect the blood concentrations of warfarin in rats, immunoblotting was employed to examine protein levels, qRT-PCR to detect mRNA levels, cellular immunofluorescence to detect the localization of NR1I3, and dual luciferase to verify the binding of miR-214-3p and NR1I3. Results: PNS significantly accelerated warfarin metabolism and reduced its efficacy, accompanied by increased expression of NR1I3 and CYP2C9. Interference with NR1I3 rescued the accelerated metabolism of warfarin induce by PNS co-administration. In addition, we demonstrated that PNS significantly reduced miR-214-3p expression, whereas miR-214-3p overexpression reduced NR1I3 and CYP2C9 expression, resulting in a weakened antagonistic effect of PNS on warfarin. Additionally, we found that miR-214-3p bound directly to NR1I3 3'-UTR and significantly downregulated NR1I3 expression. Conclusion: Our study demonstrated that PNS accelerates warfarin metabolism and reduces its pharmacodynamics by downregulating miR-214-3p, leading to increased expression of its target gene NR1I3, these findings provide new insights for clinical drug applications to avoid adverse effects.

Keywords

Acknowledgement

All persons who have made substantial contributions to the work reported in the manuscript (e.g., technical help, writing and editing assistance, general support), but who do not meet the criteria for authorship, are named in the Acknowledgements and have given us their written permission to be named. If we have not included an Acknowledgements, then that indicates that we have not received substantial contributions from non-authors.

References

  1. Whitlon D, Sadowski J, Suttie J. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 1978;17(8):1371-7.
  2. Popov Aleksandrov A, Mirkov I, Ninkov M, et al. Effects of warfarin on biological processes other than haemostasis: a review. Food Chem Toxicol: an international journal published for the British Industrial Biological Research Association 2018;113:19-32.
  3. Dong T, Cui X, Song Z, et al. Chemical assessment of roots of Panax notoginseng in China: regional and seasonal variations in its active constituents. J Agric Food Chem 2003;51(16):4617-23.
  4. Liu Y, Liu T, Zhao J, et al. Phospholipase Cγ2 signalling contributes to the haemostatic effect of Notoginsenoside Ft1. J Pharm Pharmacol 2019;71(5):878-86.
  5. Qatanani M, Moore D. CAR, the continuously advancing receptor, in drug metabolism and disease. Curr Drug Metabol 2005;6(4):329-39.
  6. Mutoh S, Osabe M, Inoue K, et al. Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3). J Biol Chem 2009;284(50):34785-92.
  7. Gardner-Stephen D, Heydel J, Goyal A, et al. Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression. Drug metabolism and disposition: the biological fate of chemicals 2004;32(3):340-7.
  8. Deng Y, Wei Z, Huang M, et al. Long non-coding RNA F11-AS1 inhibits HBV-related hepatocellular carcinoma progression by regulating NR1I3 via binding to microRNA-211-5p. J Cell Mol Med 2020;24(2):1848-65.
  9. Wang Y, Yan L, Liu J, et al. αThe HNF1-regulated LncRNA HNF1-AS1 is involved in the regulation of cytochrome P450 expression in human liver tissues and Huh7 cells. J Pharmacol Exp Therapeut 2019;368(3):353-62.
  10. Illanes S, Zhou W, Heiland S, Markus Z, Veltkamp R. Kinetics of hematoma expansion in murine warfarin-associated intracerebral hemorrhage. Brain Res 2010;1320:135-42.
  11. Chen Y, Kissling G, Negishi M, Goldstein JA. The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter. J Pharmacol Exp Ther 2005;314(3):1125-33.
  12. Assenat E, Gerbal-Chaloin S, Larrey D, et al. Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology 2004;40(4):951-60.
  13. Kida K, Nakajima M, Mohri T, et al. PPARα is regulated by miR-21 and miR-27b in human liver. Pharm Res (N Y) 2011;28(10):2467-76.
  14. Zhao JJ, Lin J, Yang H, et al. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 2008;283(45):31079-86.