Kava-associated hepatotoxicity

Abstract

Kava is a shrubby herb that has been used for centuries by the Pacific Island societies as a ceremonial, medicinal, social and recreational beverage. Kava, in the form of aqueous drinks prepared from rhizome and root, was considered "safe" with only mild but reversible adverse effects. However, between 1990 and 2001, there were 82 case reports of severe liver toxicity and even a few deaths among patients consuming kava extract preparations. Due to the continued usage of kava in the U.S. as well as its importance in the Pacific Islands, it is essential to delineate any negative effects that may occur with kava intake. Kava stem peelings, which contain high amounts of the cytotoxic alkaloid pipermethystine (PM), were reportedly incorporated into commercial extract preparations and were hypothesized to have contributed to the toxic effects of kava observed in humans. PM was shown induced oxidative stress and cell death in the human hepatoma cell line, HepG2, while the active components of the kava plant called kavalactones (KL) failed to induce any changes. However, 10-week treatment of PM (2mg/kg) and kava stem peeling extract (8.7Smg/kg) in CS7BL6 mice failed to induce liver toxicity. Short term administration of PM (10mg/kg) and acetonic kava extracts (100 mg/kg), individually and in combination, also failed to induce liver toxicity in F-344. However, an initial antioxidant stress response was noted in addition to increased CYP4S0 enzyme expression. From the data obtained, kava toxicity observed in humans are likely due to a number of factors including drug interactions rather than direct liver toxicity from PM and kavalactones alone.