期刊
FASEB JOURNAL
卷 24, 期 12, 页码 4722-4732出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.10-163311
关键词
hepatocellular toxin; apoptosis; TNF-alpha, herb products; bioluminescence imaging
资金
- U.S. National Institutes of Health [P50 CA94056]
- National Natural Science Foundation of China [30572320, 30973635]
- Chinese Academy of Sciences [KSCX2-YW-R-217]
- NATIONAL CANCER INSTITUTE [P50CA094056] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR026825] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK061848] Funding Source: NIH RePORTER
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
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