Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways.
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.
Zhou
Ping
P
Division of Oncology, Washington University, School of Medicine, St. Louis, MO, USA.
Gross
Shimon
S
Liu
Ji-Hua
JH
Yu
Bo-Yang
BY
Feng
Ling-Ling
LL
Nolta
Jan
J
Sharma
Vijay
V
Piwnica-Worms
David
D
Qiu
Samuel X
SX
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020901:Kava / Q000737:chemistry*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018625:Microscopy, Atomic Force; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D018517:Plant Roots / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D005419:Flavonoids; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C452039:flavokawain B; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione