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

Abstract

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.

Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification

“…3), demonstrating that DHM does not inhibit the reductive formation of NNAL from NNK. Results from numerous studies suggest that kavalactones can directly inhibit cytochrome 450 enzymes or indirectly regulate cytochrome 450 enzymes via transcriptional induction (Ma et al, 2004;Zou et al, 2004;Lim et al, 2007;Guo et al, 2010;Li et al, 2011). DHM, one of the major kavalactones, had minimal effect on CYP2A5 enzymatic activity in the mouse liver microsomes at 10 mM.…”

“…These results overall support the mechanism that dietary DHM treatment enhances NNAL glucuronidation both in the lung and liver tissues, which may lead to increased NNAL detoxification and reduction in NNAL-derived DNA damage in A/J mice. Dietary DHM may up-regulate UGT enzyme(s) via transcriptional activation of AHR as DHM is a potential AHR agonist (Li et al, 2011) and AHR can transcriptionally activate UGTs (Bock and Bock-Hennig, 2010).…”

The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity

“…This CYP1A1 induction has been recognized to have impact on the toxicity and carcinogenicity of many environmental chemicals and drugs (Ma and Lu, 2007). Besides classes of compounds, such as polycyclic aromatic hydrocarbons, a wide array of substances has been found to induce CYP1A1, including prescription drugs, cigarette smoke, and dietary supplements (Guo et al, 2010b; Li et al, 2011; Ma and Lu, 2007). For instance, we have reported that herbal dietary supplements, such as kava and Gingko biloba, dramatically induce CYP1A1 (Guo et al, 2009; Guo et al, 2010a; Guo et al, 2010c; Li et al, 2011).…”

“…Besides classes of compounds, such as polycyclic aromatic hydrocarbons, a wide array of substances has been found to induce CYP1A1, including prescription drugs, cigarette smoke, and dietary supplements (Guo et al, 2010b; Li et al, 2011; Ma and Lu, 2007). For instance, we have reported that herbal dietary supplements, such as kava and Gingko biloba, dramatically induce CYP1A1 (Guo et al, 2009; Guo et al, 2010a; Guo et al, 2010c; Li et al, 2011). It may be helpful for the patient administered amiodarone to take precautions to avoid the activation of CYP 1A1 as a result of their use of such dietary supplements or other CYP 1A1 inducers, as this could potentially affect the metabolism of amiodarone and its cytotoxicity.…”

Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells

“…Cell viability was assessed using a tetrazolium reduction assay (MTS, Cell Titer 96 Aqueous Non-Radioactive Cell Proliferation Assay, Promega) as previously described (Li et al ., 2011). …”