The in vitro metabolism of flavokawains A, B, and C (FKA, FKB, FKC), methoxylated chalcones from Piper methysticum, was examined using human liver microsomes. Phase I metabolism and phase II ...metabolism (glucuronidation) as well as combined phase I+II metabolism were studied. For identification and structure elucidation of microsomal metabolites, LC-HRESIMS and NMR techniques were applied. Major phase I metabolites were generated by demethylation in position C-4 or C-4′ and hydroxylation predominantly in position C-4, yielding FKC as phase I metabolite of FKA and FKB, helichrysetin as metabolite of FKA and FKC, and cardamonin as metabolite of FKC. To an even greater extent, flavokawains were metabolized in the presence of uridine diphosphate (UDP) glucuronic acid by microsomal UDP-glucuronosyl transferases. For all flavokawains, monoglucuronides (FKA-2′-O-glucuronide, FKB-2′-O-glucuronide, FKC-2′-O-glucuronide, FKC-4-O-glucuronide) were found as major phase II metabolites. The dominance of generated glucuronides suggests a role of conjugated chalcones as potential active compounds in vivo.
An ultra-high-performance liquid chromatographic (UHPLC) separation was developed for six kava pyrones (methysticin, dihydromethysticin (DHM), kavain, dihydrokavain (DHK), desmethoxyyangonin (DMY), ...and yangonin), two unidentified components, and three Flavokavains (Flavokavain A, B, and C) in
(kava). The six major kavalactones and three flavokavains are completely separated (R
> 1.5) within 15 min using a HSS T3 column and a mobile phase at 60 °C. All the peaks in the LC chromatogram of kava extract or standard solutions were structurally confirmed by LC-UV-MS/MS. The degradations of yangonin and flavokavains were observed among the method development. The degradation products were identified as cis-isomerization by MS/MS spectra. The isomerization was prevented or limited by sample preparation in a non-alcoholic solvent or with no water. The method uses the six kava pyrones and three flavokavains as external standards. The quantitative calibration curves are linear, covering a range of 0.5⁻75 μg/mL for the six kava pyrones and 0.05⁻7.5 μg/mL for the three flavokavains. The quantitation limits for methysticin, DHM, kavain, DHK, DMY, and yangonin are approximately 0.454, 0.480, 0.277, 0.686, 0.189, and 0.422 μg/mL. The limit of quantification (LOQs) of the three flavokavains are about 0.270, 0.062, and 0.303 μg/mL for flavokavain C (FKC), flavokavain A (FKA), and flavokavain B (FKB). The average recoveries at three different levels are 99.0⁻102.3% for kavalactones (KLs) and 98.1⁻102.9% for flavokavains (FKs). This study demonstrates that the method of analysis offers convenience and adequate sensitivity for determining methysticin, DHM, kavain, DHK, yangonin, DMY, FKA, FKB, and FKC in kava raw materials (root and CO₂ extract) and finished products (dry-filled capsule and tablet).
Kava kava (Piper methysticum) is a medicinal plant containing kavalactones that exert potent sedative, analgesic and anti-stress action. However, their pharmacological effects and molecular targets ...remain poorly understood. The zebrafish (Danio rerio) has recently emerged as a powerful new model organism for neuroscience research and drug discovery. Here, we evaluate the effects of acute and chronic exposure to kava and kavalactones on adult zebrafish anxiety, aggression and sociality, as well as on their neurochemical, neuroendocrine and genomic responses. Supporting evolutionarily conserved molecular targets, acute kava and kavalactones evoked dose-dependent behavioral inhibition, upregulated brain expression of early protooncogenes c-fos and c-jun, elevated brain monoamines and lowered whole-body cortisol. Chronic 7-day kava exposure evoked similar behavioral effects, did not alter cortisol levels, and failed to evoke withdrawal-like states upon discontinuation. However, chronic kava upregulated several microglial (iNOS, Egr-2, CD11b), astrocytal (C3, C4B, S100a), epigenetic (ncoa-1) and pro-inflammatory (IL-1β, IL-6, TNFa) biomarker genes, downregulated CD206 and IL-4, and did not affect major apoptotic genes in the brain. Collectively, this study supports robust, evolutionarily conserved behavioral and physiological effects of kava and kavalactones in zebrafish, implicates brain monoamines in their acute effects, and provides novel important insights into potential role of neuroglial and epigenetic mechanisms in long-term kava use.
•Kava (Piper methysticum) is a medicinal plant containing kavalactones with potent neuroactive effects.•However, their pharmacological effects and molecular targets remain poorly understood.•Zebrafish (Danio rerio) is a new powerful model organism for neuroscience and drug discovery.•Acute kava evoked overt sedation, elevated brain monoamines and reduced whole-body cortisol levels.•Chronic kava evoked similar behavioral effects and upregulated neuroglial biomarker genes
Kava, the extract of the roots of
, has been traditionally consumed in the South Pacific islands for its natural relaxing property. Epidemiological data suggests that kava consumption may reduce ...human cancer risk, and
and
models suggest chemopreventive potential against carcinogen-induced tumorigenesis. Therefore, knowledge about its molecular mechanisms and responsible ingredient(s) for these beneficial properties will better guide kava's use for the management of these disorders. Psychological stress typically results in increased production of stress hormones, such as norepinephrine (NE), which activate adrenergic receptors (ARs). Psychological stress has also been associated with increased cancer incidence and poor clinical outcomes in cancer patients. Mechanistically, binding of NE to ARs induces intracellular calcium influx, which activates downstream signaling pathways involved in both stress and cancer development. In this study, we characterized the effect of kava and its components, 3 fractions and 6 major kavalactones, on NE-induced intracellular calcium influx in H1299, a human non-small cell lung carcinoma cell line. Results show that kava extract effectively inhibits NE-mediated intracellular calcium influx in H1299 cells, potentially through antagonizing
-AR signaling. This inhibitory activity is recapitulated by the major kavalactones in kava. Among the 6 major kavalactones, DHK demonstrated the best potency. Taken together, our study suggests a novel mechanism through which kava and its ingredients potentially offer the anxiolytic and cancer-preventive activity.
Explains a feasibility study that combined a Pacific respect-based cultural methodology with a counter-hegemonic development theory to create a post-development methodological framework (PDMF) which ...was then used to guide the culturally ethical use of Western psychometric measures at a naturalistic kava-use setting, to study the impact of kava use on driver safety among both Pacific and non-Pacific peoples. Reports on the usefulness of the Brain Gauge tool (a somatosensory psychometric measure) when used in a naturalistic test setting and with a faikava methodology. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
The association of kava products with liver-related health risks has prompted regulatory action in many countries. We used a genome-wide gene expression approach to generate global gene expression ...profiles from the livers of male B6C3F1 mice administered kava extract by gavage for 14
weeks, and identified the differentially expressed drug metabolizing genes in response to kava treatments. Analyses of gene functions and pathways reveal that the levels of significant numbers of genes involving drug metabolism were changed and that the pathways involving xenobiotics metabolism, Nrf2-mediated oxidative stress response, mitochondrial functions and others, were altered. Our results indicate that kava extract can significantly modulate drug metabolizing enzymes, potentially leading to herb–drug interactions and hepatotoxicity.
•Fast quality control of kava extract samples.•First detection of flavokavins in acetonic extracts using HPTLC.•Reliable and accurate differentiation of dry raw material originating from acceptable ...and unsuitable cultivars.
Kava (Piper methysticum) is used to prepare the traditional beverage of the Pacific islands. In Europe, kava has been suspected to cause hepatoxicity with flavokavin B (FKB) considered as a possible factor. The present study describes an HPTLC protocol for rapid screening of samples. The objectives are: to detect the presence of flavokavins in extracts and to compare the FKB levels in different cultivars. Overall, 172 samples originating from four cultivars groups (noble, medicinal, two-days and wichmannii), were analysed. Results indicate that the ratio FKB/kavalactones is much higher in two-days (0.39) and wichmannii (0.32) compared to nobles (0.09) and medicinal cultivars (0.10). For each group, the ratios flavokavins/kavalactones do not change significantly between roots, stumps or basal stems and among clones, indicating that they are genetically controlled. This protocol has good accuracy and is cost efficient for routine analysis. We discuss how it could be used for quality control.
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•New kava analogues as agents for treatment of periodontal diseases.•15 was found to significantly reduce P. gingivalis induced TNF-α production.•Corresponding vinyl amide analogues ...were inactive.
Six kava analogues of the structural type 3-oxocyclohex-1-en-1-yl benzoates (and corresponding benzamides) were synthesized and evaluated for their affect on periodontal deconstruction in collagen anti-body primed oral gavage model of periodontitis. The compounds were prepared through an acylation or amidation of the enolizable cyclic 1,3-diketone. We have learned that three of the analogues are responsible for the reduction of inflammatory cell counts within soft tissue. These novel kava-like molecules where the lactone is replaced by an α,β-unsaturated ketone show promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis.
Kava (Piper methysticum), a perennial shrub native to the South Pacific islands, has been used to relieve anxiety. Recently, several cases of severe hepatotoxicity have been reported from the ...consumption of dietary supplements containing kava. It is unclear whether the kava constituents, kavalactones, are responsible for the associated hepatotoxicity. To investigate the key components responsible for the liver toxicity, bioassay-guided fractionation was carried out in this study. Kava roots, leaves, and stem peelings were extracted with methanol, and the resulting residues were subjected to partition with a different polarity of solvents (hexane, ethyl acetate, n-butanol, and water) for evaluation of their cytotoxicity on HepG2 cells based on the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and lactate dehydrogenase and aspartate aminotransferase enzyme leakage assays. Organic solvent fractions displayed a much stronger cytotoxicity than water fractions for all parts of kava. The hexane fraction of the root exhibited stronger cytotoxic effects than fractions of root extracted with other solvents or extracts from the other parts of kava. Further investigations using bioassay-directed isolation and analysis of the hexane fraction indicated that the compound responsible for the cytotoxicity was flavokavain B. The identity of the compound was confirmed by 1H and 13 C NMR and MS techniques. Keywords: Kava; Piper methysticum; cytotoxicity; Kava toxicity; flavokavain
Kava (Piper methysticum) is an effective anxiolytic that has been withdrawn from various consumer markets in European countries due to concerns over its hepatotoxicity. It is plausible that the ...reported hepatotoxicity may be due in part to plant substitution, or an incorrect cultivar, or plant parts being used (such as leaves or bark); thus both the plant chemotype and the plant part used may be critical factors. If re-institution of kava in the EU is to occur, more evidence is required to determine its safety and efficacy. Furthermore, according to current evidence, the study of traditional water soluble rhizome extracts using a noble cultivar of kava may be advised. The Kava Anxiety-Lowering Medication (KALM) project is due to start in late 2010 to address these considerations. The KALM project uses an aqueous rhizome extract of a noble cultivar of kava in participants with generalised anxiety and Generalised Anxiety Disorder (GAD). The project comprises of 1) an acute RCT, kava (180 mg of kavalactones) versus oxazepam and placebo in 20 anxious people, testing effects on cognition, mood, anxiety, and driving; 2) an 8-week RCT comparing kava (120 mg kavalactones) versus placebo in 100 patients with GAD. To assess differences between dosages, non-responders at 3 weeks will be titrated to 240 mg of kavalactones. The project will also assess the effects of kava on liver function tests and its side effects profile. A novel component of the project is the pharmacogenomic exploration of phenotypical responses (GABA system and cytochrome P450 markers). The results of the study may be of benefit to sufferers of anxiety and the future economy of the Pacific islands, potentially providing an important step in the way forward with kava.
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