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Toxicity evaluation

Mechanisms of action to explain kava’s pharmacological and toxicological properties are still incompletely understood. Known side effects are relatively mild and include allergic reactions and gastrointestinal complaints. Kava dermopathy is a well-recognized symptom in heavy kava users. It appears after weeks of ingestion as a scaly rash; however, the skin returns to normal upon cessation. There is an apparent dose–response relationship and the prevalence in heavy kava users has been reported to be 78%. Amore serious issue is suspectedkava-induced hepatotoxicity. This has resulted in extensive studies of kava lactones, chalcones, and alkaloids. To date, there are no indisputable explanations and, due to the lack of dose dependency, kava-induced hepatotoxicity has been classified as idiosyncratic, possibly with involvement of the immune system. Ninety-three cases of suspected kava-induced hepatotoxicity have been reviewed by the World Health Organization (WHO). However, in most cases the information was inadequate to determine whether hepatotoxicity was caused by kava. The reported symptoms were hepatitis, hepatic failure, cholestatic hepatitis, jaundice, abnormal hepatic function, and cirrhosis. The outcome in seven of the reviewed cases was death and 14 of the cases resulted in liver transplant. The mean duration to onset was 111 days and positive rechallenge tests were seen in five patients. The form of kava use in the South Pacific and in Aboriginal communities is apparently not associated with the hepatotoxicity reported in Western countries. Elevated liver enzymes (gammaglutamyl transferase (GGT) and alkaline phosphatase (ALP)) have been reported in these kava users, consuming an average 118 g week-1. The symptoms were reversible upon cessation. Involvement of glutathione (GSH) and possibly depletion of endogenous GSH has been proposed to be involved in the toxic mechanism. A recent study revealed that in vitro toxicity of kava and acetaminophen (APAP) was intensified by coadministration. Toxicity of APAP is due to formation of a reactive metabolite causing depletion of GSH. The increase in toxicity when kava was coadministered suggests that GSH somehow could be involved in detoxification of kava. The possibility of kava acting as an inhibitor of specific metabolic enzymes has been investigated. In vitro results have shown that kava is indeed capable of altering the metabolic capacity of a number of P-450 enzymes; however, the relation to hepatotoxicity remains unclear. Flavokavains have been identified as the most potent cytotoxic compounds in kava. Recently, the flavokavains gained attention as they have shown apoptotic effects on cancer cells. Among others, the targets include nuclear factor kappa beta (NF-kB), Bax, reactive oxygen species, and growth arrest and DNA-damage-inducible protein (GADD153). Like the lactones, these compounds have very low solubility in water. Thus, an organic extract would be expected to contain much higher concentrations than an aqueous extract. The toxicity of flavokavains is yet to be examined in vivo. Poor quality kava products have been accused of being involved in the increased prevalence of kava-induced hepatotoxicity in Western countries. Due to the popularity boom, aerial parts of the shrub allegedly have been included in the material used to produce commercial kava preparations. Aerial parts are generally avoided in the South Pacific as they contain a relatively high amount of alkaloids such as pipermethystine, which has been reported to decrease cellular ATP levels and mitochondrial membrane potential and induce apoptosis in human HepG2 cells. Pipermethystine has, however, not been identified in commercial products in clinically significant amounts. Another aspect of poor quality kava has recently been addressed. It has been proposed that, due to high temperatures and humidity in the South Pacific, mold would be able to develop rapidly in kava plant material not stored correctly. It has been suggested consequently that hepatotoxins including aflatoxins could be present in poor quality kava plant material.