Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappa B 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 (LD50 = 15.3 +/- 0.2 mu M) and L-02 (LD50 = 32 mu M) cells. Hepatocellular toxicity of FKB is mediated by induction of oxidative stress, depletion of reduced glutathione (GSH), inhibition of IKK activity leading to NF-kappa B transcriptional blockade, and constitutive TNF-alpha-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-kappa B transcriptional activity in vivo and severe liver damage. Surprisingly, replenishment with exogenous GSH normalizes both TNF-alpha-dependent NF-kappa B 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, P., Gross, S., Liu, J.-H., Yu, B.-Y., Feng, L.-L., Nolta, J., Sharma, V., Piwnica-Worms, D., Qiu, S. X. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappa B and MAPK signaling pathways. FASEB J. 24, 4722-4732 (2010). www.fasebj.org