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

Abstract

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.

Progress in the research of GSH in cells

“…Recent studies have suggested that GSH depletion and post-translational modification of proteins through glutathionylation are related to cell death. GSH is crucial to counteract oxidative stress-induced liver injury as it detoxifies some hepatotoxins and inhibits cell damage induced by hepatotoxins (e.g., Flavokawain B, pyrrolizidine alkaloid, aflatoxin B1 and ethanol) [26][27][28]. In addition to hepatotoxins, GSH is recognized by compounds such as gallic acid, which is widely distributed in plants and foods, and can induce Hela cell death in relation to the ROS and GSH level [29].…”

Adverse Effects of Drugs and Toxins on the Liver

“…The principle pharmacological activities of Kava are due to kavalactones, where kavain is the most important. Kavalactones can form electrophilic, quinone metabolites, potentially leading to GSH depletion and oxidative stress (Zhou et al, 2010). Furthermore, kavalactones inhibit CYP-450 enzymes in vitro (Mathews et al, 2002).…”

“…Recently it was reported that a piperidine alkaloid, pipermethystine (PM), induces apoptosis in human hepatoma HepG2 cells (Nerurkar et al, 2004), but fails to induce hepatic toxicity in vivo (Lim et al, 2007). Furthermore, pipermethystine is not present in significant quantities in roots and rhizomes from the plant used in herbal medicines (Zhou et al, 2010). A new report suggest that the principle damaging substituent is flavokawain B, a lipohophilic chalcone (Zhou et al 2010).…”

“…Furthermore, pipermethystine is not present in significant quantities in roots and rhizomes from the plant used in herbal medicines (Zhou et al, 2010). A new report suggest that the principle damaging substituent is flavokawain B, a lipohophilic chalcone (Zhou et al 2010). The authors suggest that flavokawain B can through induction of oxidative stress and depletion of GSH modulate signalling pathways including JNK to induce cellular apoptosis.…”

Yangonin Blocks Tumor Necrosis Factor-α–Induced Nuclear Factor-κB–Dependent Transcription by Inhibiting the Transactivation Potential of the RelA/p65 Subunit

“…This compound was shown to have not only potent antioxidant or free radical-scavenging activities, but also the ability to inhibit cyclooxygenase enzyme cyclooxygenase-1 (COX-1) and COX-2 (7). Yangonin also inhibited LPS-and TNF-α-induced NF-κB activation (8,9); however, the molecular mechanism has not been sufficiently explained. In present study, we investigated the effects of yangonin on the NF-κB activation pathway induced by TNF-α.…”