Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways

FASEB J. 2010 Dec;24(12):4722-32. doi: 10.1096/fj.10-163311. Epub 2010 Aug 9.


Kava (Piper methysticum Foster, Piperaceae) organic solvent-extract has been used to treat mild to moderate anxiety, insomnia, and muscle fatigue in Western countries, leading to its emergence as one of the 10 best-selling herbal preparations. However, several reports of severe hepatotoxicity in kava consumers led the U.S. Food and Drug Administration and authorities in Europe to restrict sales of kava-containing products. Herein we demonstrate that flavokawain B (FKB), a chalcone from kava root, is a potent hepatocellular toxin, inducing cell death in HepG2 (LD(50)=15.3 ± 0.2 μM) and L-02 (LD(50)=32 μM) cells. Hepatocellular toxicity of FKB is mediated by induction of oxidative stress, depletion of reduced glutathione (GSH), inhibition of IKK activity leading to NF-κB transcriptional blockade, and constitutive TNF-α-independent activation of mitogen-activated protein kinase (MAPK) signaling pathways, namely, ERK, p38, and JNK. We further demonstrate by noninvasive bioluminescence imaging that oral consumption of FKB leads to inhibition of hepatic NF-κB transcriptional activity in vivo and severe liver damage. Surprisingly, replenishment with exogenous GSH normalizes both TNF-α-dependent NF-κB as well as MAPK signaling and rescues hepatocytes from FKB-induced death. Our data identify FKB as a potent GSH-sensitive hepatotoxin, levels of which should be specifically monitored and controlled in kava-containing herb products.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Flavonoids / pharmacology*
  • Glutathione / metabolism*
  • Hep G2 Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • Kava / chemistry*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Atomic Force
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Oxidative Stress / drug effects*
  • Plant Roots / chemistry*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology


  • Flavonoids
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • flavokawain B
  • I-kappa B Kinase
  • Mitogen-Activated Protein Kinases
  • Glutathione