2017 ASHS Annual Conference

Kava (Piper methysticum Forst. f., Piperaceae) has been utilized for centuries in Pacific Island communities for medicinal, social and ceremonial purposes. Traditional methods of kava preparation involve the extraction of powdered material to produce an aqueous emulsion that is consumed by drinking. Kava has a number of effects (sedative, anticonvulsant, immunomodulatory, and others). These are attributed to the secondary metabolites present in kava extracts, which include several unique lactones (kavalactones), alkaloids and chalcones (flavokawains). Notably, flavokawains A and B (FKA, FKB) possess anticancer activity in mammalian cell culture and in preclinical models of breast, bladder and prostate cancers. However, flavokawains have also been suspected to either cause, or to facilitate liver damage. To better understand how FKA and FKB interact with the liver, and test for any distinct effects between the two compounds, we studied their actions on the human hepatocyte cell line, HepG2. We report that FKB exhibits significant toxicity to hepatocytes at low-mid nM concentrations, but that FKA is minimally toxic over a much wider concentration range. In addition to cell toxicity, we also studied how flavokawains affect cell signaling and gene expression in hepatocytes. Both compounds cause a marked enhancement in the heat shock and antioxidant signaling pathways. These pathways mediate the expression of genes that protect against protein damage, oxidative stress, and cell death. Accordingly, we find that a brief exposure of hepatocytes to flavokawains helps to prevent cell death caused by subsequent oxidative stress. Of the two compounds, FKA elicits a greater degree of protection against oxidative stress in human liver cells, and also has no apparent toxicity at the concentrations tested. We therefore suspect that cultivars with high FKA and low FKB content may be most appropriate if to be used or promoted for cancer chemoprevention, in order to minimize risk of hepatoxic effects from FKB. Further testing will be necessary to evaluate the full significance of FKA exposure on the liver.