High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats

Yamazaki, Yuko; Hashida, Hiroko; Arita, Anna; Hamaguchi, Keiko; Shimura, Fumio

doi:10.1016/j.fct.2008.09.052

Cited by 25 publications

(24 citation statements)

References 35 publications

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“…Based on the results of microarray, Taq-Man assay, and Phalanx Mouse OneArray, the significant detected gene expression changes of note included Gstal, Gsta2, Cyp1a1, Cyp1a2, Cyp2a5, Cyp2b20, Cyp2c55, and Cyp3a11. The increased expression of Cyp1a1 upon the exposure of kava is in concordance with our previous finding (Guo et al, 2009) and the report by Yamazaki et al (2008) with rat liver tissue.…”

Section: Discussionsupporting

confidence: 93%

Gene expression profiling in male B6C3F1 mouse livers exposed to kava identifies – Changes in drug metabolizing genes and potential mechanisms linked to kava toxicity

Guo

Shi

Dial

et al. 2010

Food and Chemical Toxicology

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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.

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Section: Discussionsupporting

confidence: 93%

Gene expression profiling in male B6C3F1 mouse livers exposed to kava identifies – Changes in drug metabolizing genes and potential mechanisms linked to kava toxicity

Guo

Shi

Dial

et al. 2010

Food and Chemical Toxicology

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“…A study using human hepatocytes demonstrated that kava increased CYP3A4 mRNA level and activated pregnane X receptor (PXR) to mediate CYP3A4 induction (Raucy, 2003). Most recently, studies, including ours, have reported that kava induced the expression of CYP1A1 (Guo et al, 2009(Guo et al, , 2010bYamazaki et al, 2008;Yueh et al, 2005). For example, kava markedly enhanced CYP1A1 mRNA expression (75-220 fold) as well as CYP1A1 protein expression with a high dose treatment (equivalent to approximately 380 mg/kg/day of kavalactones) in rats for 8 days (Yamazaki et al, 2008) and moderately induced CYP1A1 in HepG2 cells (Yueh et al, 2005).…”

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confidence: 63%

Methysticin and 7,8-Dihydromethysticin are Two Major Kavalactones in Kava Extract to Induce CYP1A1

Mei

et al. 2011

Toxicological Sciences

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Kava is a plant traditionally used for making beverages in Pacific Basin countries and has been used for the treatment of nervous disorders in the United States. The pharmacological activity of kava is achieved through kavalactones in kava extract, which include kawain, 7,8-dihydrokawain, yangonin, 5,6-dehydrokawain, methysticin, and 7,8-dihydromethysticin. Recent studies have shown that kava extract induces hepatic CYP1A1 enzyme; however, the mechanisms of CYP1A1 induction have not been elucidated, and the kavalactones responsible for CYP1A1 induction have not yet been identified. Using a combination of biochemical assays and molecular docking tools, we determined the functions of kava extract and kavalactones and delineated the underlying mechanisms involved in CYP1A1 induction. The results showed that kava extract displayed a concentration-dependent effect on CYP1A1 induction. Among the six major kavalactones, methysticin triggered the most profound inducing effect on CYP1A1 followed by 7,8-dihydromethysticin. The other four kavalactones (yangonin, 5,6-dehydrokawain, kawain, and 7,8-dihydrokawain) did not show significant effects on CYP1A1. Consistent with the experimental results, in silico molecular docking studies based on the aryl hydrocarbon receptor (AhR)-ligand binding domain homology model also revealed favorable binding to AhR for methysticin and 7,8-dihydromethysticin compared with the remaining kavalactones. Additionally, results from a luciferase gene reporter assay suggested that kava extract, methysticin, and 7,8-dihydromethysticin were able to activate the AhR signaling pathway. Moreover, kava extract-, methysticin-, and 7,8-dihydromethysticin-mediated CYP1A1 induction was blocked by an AhR antagonist and abolished in AhR-deficient cells. These findings suggest that kava extract induces the expression of CYP1A1 via an AhR-dependent mechanism and that methysticin and 7,8-dihydromethysticin contribute to CYP1A1 induction. The induction of CYP1A1 indicates a potential interaction between kava or kavalactones and CYP1A1-mediated chemical carcinogenesis.

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“…In the two latter countries, the kava drugs contained also solubilizers such as macrogol, craspavidon, mentha oil, methyl acryl acid polymer and polysorbate polyols to enhance gastrointestinal absorption of the lipid soluble kavalactones (Teschke, ), which could also facilitate the intestinal uptake of co‐concentrated AFs possibly contained in the drugs. When both kavalactones and AFs have reached the liver, interactions of kavalactones at the site of the hepatic microsomal cytochrome P450 are possible (Yamazaki et al , ), since AFs are substrates of cytochrome P450 (Guo et al , ). Certainly, further studies are necessary to disprove or even prove the working hypothesis outlined above (Table ), considering also that testing of AFs was basically an essential part of the specifications of the kava products licensed as drugs in Europe.…”

Section: Toxicological Studiesmentioning

confidence: 99%

Kava and Kava Hepatotoxicity: Requirements for Novel Experimental, Ethnobotanical and Clinical Studies Based on a Review of the Evidence

Teschke

Qiu

Xuan

et al. 2011

Phytotherapy Research

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Kava hepatotoxicity is a well described disease entity, yet there is uncertainty as to the culprit(s). In particular, there is so far no clear evidence for a causative role of kavalactones and non-kavalactone constituents, such as pipermethystine and flavokavain B, identified from kava. Therefore, novel enzymatic, analytical, toxicological, ethnobotanical and clinical studies are now required. Studies should focus on the identification of further potential hepatotoxic constituents, considering in particular possible adulterants and impurities with special reference to ochratoxin A and aflatoxins (AFs) producing Aspergillus varieties, which should be urgently assessed and published. At present, Aspergillus and other fungus species producing hepatotoxic mycotoxins have not yet been examined thoroughly as possible contaminants of some kava raw materials. Its occurence may be facilitated by high humidity, poor methods for drying procedures and insufficient storage facilities during the time after harvest. Various experimental studies are recommended using aqueous, acetonic and ethanolic kava extracts derived from different plant parts, such as peeled rhizomes and peeled roots including their peelings, and considering both noble and non-noble kava cultivars. In addition, ethnobotanical studies associated with local expertise and surveillance are required to achieve a good quality of kava as the raw material. In clinical trials of patients with anxiety disorders seeking herbal anxiolytic treatment with kava extracts, long-term safety and efficacy should be tested using traditional aqueous extracts obtained from peeled rhizomes and peeled roots of a noble kava cultivar, such as Borogu, to evaluate the risk: benefit ratio. Concomitantly, more research should be conducted on the bioavailability of kavalactones and non-kavalactones derived from aqueous kava extracts. To be on the side of caution and to ensure lack of liver injury, kava consuming inhabitants of the kava producing or importing South Pacific islands should undergo assessment of their liver function values and serum aflatoxin levels. The primary aim is to achieve a good quality of kava raw material, without the risk of adulterants and impurities including ochratoxin A and AFs, which represent the sum of aflatoxin B1, B2, G1 and G2. Although it is known that kava may naturally be contaminated with AFs, there is at present no evidence that kava hepatotoxicity might be due to aflatoxicosis. However, appropriate studies have yet to be done and should be extended to other mould hepatotoxins, with the aim of publishing the obtained results. It is hoped that with the proposed qualifying measures, the safety of individuals consuming kava will substantially be improved.

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High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats

Cited by 25 publications

References 35 publications

Gene expression profiling in male B6C3F1 mouse livers exposed to kava identifies – Changes in drug metabolizing genes and potential mechanisms linked to kava toxicity

Gene expression profiling in male B6C3F1 mouse livers exposed to kava identifies – Changes in drug metabolizing genes and potential mechanisms linked to kava toxicity

Methysticin and 7,8-Dihydromethysticin are Two Major Kavalactones in Kava Extract to Induce CYP1A1

Kava and Kava Hepatotoxicity: Requirements for Novel Experimental, Ethnobotanical and Clinical Studies Based on a Review of the Evidence

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