Article

Kava extract, an herbal alternative for anxiety relief, potentiates acetaminophen-induced cytotoxicity in rat hepatic cells

Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
Phytomedicine: international journal of phytotherapy and phytopharmacology (Impact Factor: 3.13). 03/2011; 18(7):592-600. DOI: 10.1016/j.phymed.2011.02.006
Source: PubMed

ABSTRACT

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 the US, the FDA has issued warnings about the potential adverse effects of kava, but kava dietary supplements are still available to consumers. In this study, we tested the potential of kava extract to potentiate APAP-induced hepatocyte cytotoxicity. In rat primary hepatocytes, co-treatment with kava and APAP caused 100% loss of cell viability, while the treatment of kava or APAP alone caused ∼50% and ∼30% loss of cell viability, respectively. APAP-induced glutathione (GSH) depletion was also potentiated by kava. 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. In addition, similar findings were obtained from a cultured rat liver cell line, clone-9. These observations indicate that kava potentiates APAP-induced cytotoxicity by increasing the magnitude of GSH depletion, resulting in oxidative stress and mitochondrial dysfunction, ultimately leading to cell death. These results highlight the potential for drug-dietary supplement interactions even with widely used over-the-counter drugs.

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    • "To overcome the availability, quality and interindividual variability issues of human cells, numerous studies have been conducted using APAP-exposed primary rodent hepatocytes, with the best results obtained with those originating from mice (Adamson and Harman, 1993; Bajt et al., 2004; Burcham and Harman, 1991; Burke et al., 2010; Kon et al., 2004, 2007; Ni et al., 2012; Reid et al., 2005; Shen et al., 1992). Although the in vivo rat model has limited relevance for humans compared to mice, similar concentrationdependent GSH depletion, oxidant stress and cytotoxicity are observed in their corresponding hepatocyte cultures (Ellouk-Achard et al., 1995; McGill et al., 2012b; Rousar et al., 2009; Yang and Salminen, 2011). Likewise, cultured mouse and human hepatocytes show comparable GSH depletion, mitochondrial protein adduct formation, p-JNK activation and necrosis, albeit occurring at earlier time points and with overall lower protein binding in the rodent in vitro setting. "
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