In Vitro Toxicity of Kava Alkaloid, Pipermethystine, in HepG2 Cells Compared to Kavalactones

Abstract

Kava herbal supplements have been recently associated with acute hepatotoxicity, leading to the ban of kava products in approximately a dozen countries around the world. It is suspected that some alkaloids from aerial kava may have contributed to the problem. Traditionally, Pacific Islanders use primarily the underground parts of the shrub to prepare the kava beverage. However, some kava herbal supplements may contain ingredients from aerial stem peelings. The aim of this study was to test the in vitro effects of a major kava alkaloid, pipermethystine (PM), found mostly in leaves and stem peelings, and kavalactones such as 7,8-dihydromethysticin (DHM) and desmethoxyyangonin (DMY), which are abundant in the roots. Exposure of human hepatoma cells, HepG2, to 100 microM PM caused 90% loss in cell viability within 24 h, while 50 microM caused 65% cell death. Similar concentrations of kavalactones did not affect cell viability for up to 8 days of treatment. Mechanistic studies indicate that, in contrast to kavalactones, PM significantly decreased cellular ATP levels, mitochondrial membrane potential, and induced apoptosis as measured by the release of caspase-3 after 24 h of treatment. These observations suggest that PM, rather than kavalactones, is capable of causing cell death, probably in part by disrupting mitochondrial function. Thus, PM may contribute to rare but severe hepatotoxic reactions to kava.

Kavalactones Protect Neural Cells against Amyloid β Peptide-Induced Neurotoxicity via Extracellular Signal-Regulated Kinase 1/2-Dependent Nuclear Factor Erythroid 2-Related Factor 2 Activation

“…1). These results are consistent with the literature describing kava-kava and particularly purified kavalactones as virtually nontoxic substances (Clouatre, 2004;Nerurkar et al, 2004;Sorrentino et al, 2006).…”

“…There have been several reports of rare but severe liver toxicity, including liver failure in some people who have used dietary supplements containing kava extract. In this context, Nerurkar et al (2004) showed toxicity for the kava alkaloid pipermethystine but not for kavalactones such as methysticin and yangonin. This study suggests that pipermethystine, rather than kavalactones, is responsible for the hepatotoxic reactions to kava.…”

Adult adipose-derived stem cell attachment to biomaterials

“…ATP provides information about sublethal cell damage because the production of ATP may be transiently depressed by many forms of cell stress. ATP levels measured here were within a normal range, similar to that seen in studies of other cell types [10,11]. Additionally, caspase-3, a member of the caspase family of cysteine proteases, is a known early indicator of apoptosis.…”

Toxicity of Kava Kava

“…However, some kava herbal supplements may contain pipermethystine, which is an ingredient from aerial stem peelings. Pipermethystine was found to decrease cellular ATP levels and mitochondrial membrane potential and induce apoptosis as measured by the release of caspase-3 in cultured human hepatoma cells, HepG2 (59). These results suggest that pipermethystine, rather than kavalactones, is capable of causing cell death (59).…”