Kava Extract, an Herbal Alternative for Anxiety Relief, Potentiates Acetaminophen-Induced Hepatotoxicity

The widely-used over-the-counter analgesic acetaminophen (APAP) is the leading cause of acute liver failure in the United States and due to this high incidence, a recent FDA Advisory Board recommended lowering the maximum dose of APAP. Kava herbal dietary supplements have been implicated in several human liver failure cases leading to the ban of kava-containing products in several Western countries. In this study, we tested the potential of kava extract to potentiate APAP-induced hepatotoxicity in mice and probe mechanisms of the interaction. Based on serum ALT and AST levels, kava potentiated APAP-induced hepatotoxicity when kava was administered orally, once daily for 3 days at 2000mg/kg prior to a single oral dose of APAP (150mg/kg). Administration of a single dose of kava 6 hours after the APAP dose did not affect APAP-induced hepatotoxicity. A series of studies was conducted in primary rat hepatocytes to probe potential mechanisms of the kava-APAP interaction. Kava potentiated APAP-induced cytotoxicity and glutathione (GSH) depletion. Co-exposure to kava decreased cellular ATP concentrations, increased the formation of reactive oxygen species, and caused mitochondrial damage as indicated by a decrease in mitochondrial membrane potential. These observations indicate that kava potentiates APAP-induced toxicity by increasing the magnitude of GSH depletion, resulting in oxidative stress and mitochondrial dysfunction, ultimately leading to hepatocyte damage and cell death. These results highlight the potential for drug-dietary supplement interactions even with widely used over-the-counter drugs.