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BP J 5-98849 Nouméa (2) ChemTox-67400 Strasbourg (3) Institut de Recherche pour le Développement (4) Centre Hospitalier Spécialisé, Nouméa-Nouvelle-Calédonie

-Purpose:Kava is a traditional Pacific beverage made from the root of Piper methysticum. It is mainly used for its sedative properties due to lipophilic lactones called kavalactones. Various preparations or medications made from this plant can be purchased via the internet. Kava action mechanisms include cell membrane stabilisation, inhibition of intracellular Ca 2+ increase and enzyme inactivation. Chronic or heavy kava consumption results in the skin taking on a scaly aspect. Biologically, an isolated increase in serum gamma-glutamyltransferase is apparent. Cases of sudden death after heavy kava sessions have occurred in Australia, and nine cases in New Caledonia were reported by our forensic laboratory during the 2000−mid-2013 period. No clear explanation has been given. We describe the possible action mechanism. Methods: We monitored 116 heavy kava drinkers. A multiple-probe drug cocktail was used on six other volunteers, all heavy and chronic kava drinkers, before and after kava abstinence to carry out CYP450 phenotyping. Results: The heavy chronic drinkers showed an isolated increase in GGT without any biological or clinical abnormality other than scaly skin. With the multiple-probe drug cocktail an inhibition of the CYP1A2 isoenzyme was demonstrated. In kava dermopathy a lack of epithelial nitric oxide production leading to an increased S-nitroso-glutathione degradation by the epithelial gamma-glutamyltransferase should be considered. Conclusions: As there are close structural and functional similarities between nitric oxide synthase (NOS) and CYP1A2, and as we have formerly demonstrated that kava inhibits CYP1A2, an inhibition of NOS in chronic kava drinkers must be studied to see if ichthyosis can be explained, and if high blood GGT level is a reflection of epithelial cell GGT activity. Furthermore, a decrease in NO bioavailability can cause myocardial and vascular dysfunctions and hypercoagulability, leading to acute coronary syndrome or ischemic stroke. This mechanism should be explored in cases of "post-kava session sudden death".Key words: Kava, abuse, ichthyosis, GGT, sudden death, NO synthase Résumé -Objectifs : Le kava est une boisson traditionnelle faite à partir du rhizome de piper methysticum. Il est principalement consommé pour ses propriétés sédatives dues à des lactones lipophiles appelées kavalactones. Des prépara-tions variées à base de kava peuvent aussi être commandées sur Internet. Les mécanismes d'action du kava comprennent une stabilisation membranaire, une inhibition de l'élévation du Ca 2+ intracellulaire et des inactivations enzymatiques. Après une consommation chronique et importante on note cliniquement un aspect écailleux de la peau. Du point de vue biologique on observe une augmentation isolée de gamma-glutamyltransférase sérique. Des cas de mort subite après consommation de kava sont survenus en Australie, et neuf cas sont survenus en Nouvelle-Calédonie durant la période de 2000 à mi-2013. Aucune explication satisfaisante n'a été apportée et nous décrivons le possibl...

Purpose Consumption of traditional aqueous kava (Piper methysticum Forst. f.) extracts is common in the Pacific region, whereas commercial products have been withdrawn in many countries due to rare but severe hepatotoxicity. Previous in‐vitro studies suggest that kavalactones are metabolized via CYP450 and that they have an inhibitory effect on these enzymes, which may be relevant for interactions as well as for the mechanism by which kava rarely causes hepatotoxicity. Methods: In a cross‐over study, 6 healthy chronic kava consumers from New Caledonia (estimated intake of kavalactones 7–27 grams per week for >6 years) received probe‐drug cocktails on two consecutive days. After complete stop of kava drinking for 4 weeks they received the same probe‐drugs again. Phenotypic trait measurements were determined for the metabolizing CYP450 enzymes at both time points. Results: Serum concentration ratios with and without kava exposure for paraxanthine/caffeine (CYP1A2) were 0.3±0.1 vs. 0.6±0.2 (mean±SD, p=0.02), for 1‐OH‐midazolam/midazolam (CYP3A4) 0.4±0.1 vs. 0.4±0.2 (p=0.75), and for 6‐OH‐chlorzoxazone/chlorzoxazone (CYP2E1) 0.9±0.6 vs. 1.4±1.1 (p=0.16). Urinary recovery ratios for debrisoquine/OH‐debrisoquine (CYP2D6) were 0.8±0.4 vs. 0.8±0.6 (p=0.82) and for mephenytoin/4‐OH‐mephenytoin (CYP2C19) 2.0±0.9 vs. 1.5±0.6 (p=0.29). Conclusion: Traditional kava drinking in high amounts inhibits CYP1A2, but does not affect CYP2D6, CYP2C19, CYP2E1 or CYP3A4 activities. Clinical Pharmacology & Therapeutics (2004) 75, P83–P83; doi: