Individual kavalactones affect the liver enzyme
CYP3A (specifically, CYP3A23 in rats) and activate the
pregnane X receptor (PXR). Among six tested kavalactones, dihydromethysticin and
desmethoxyyangonin were the only ones that significantly induced CYP3A23 expression (about 7-fold). The induction was greatly reduced or eliminated when either of these two compounds was removed from kavalactone mixtures, suggesting they are essential for the effect. Their activity was enhanced by other kavalactones, indicating a possible
synergistic or additive interaction. Both compounds increased CYP3A23
mRNA levels, but only weakly activated rat or human PXR, unlike the strong activator
pregnenolone 16α-carbonitrile (PCN). This suggests that dihydromethysticin and desmethoxyyangonin induce CYP3A23 via
transcriptional activation, likely through a PXR-independent or indirect PXR-related pathway. Kava extract induces the liver enzyme
CYP1A1 through an
aryl hydrocarbon receptor (AhR)-dependent pathway. Methysticin and 7,8-dihydromethysticin were the primary contributors, showing the strongest effects in both
biochemical assays and
molecular docking studies. The CYP1A1 induction was blocked by an AhR antagonist and absent in AhR-deficient cells. This suggests a potential interaction between kava and chemical
carcinogenesis mediated by CYP1A1. File:Benzo(a)pyrene metabolism.svg|thumb |left|540px |Metabolism of benzo[
a]pyrene yielding the
carcinogenic benzo[
a]pyren-7,8-dihydrodiol-9,10-epoxide. It exhibits
anticonvulsant,
analgesic, and
anxiolytic effects by modulating
NMDA receptors and
voltage-dependent calcium channels, and shows additive effects when combined with
kavain or the serotonin-1A agonist
ipsapirone. It has been found to act as a
GABAA receptor positive allosteric modulator and as an reversible
inhibitor of
monoamine oxidase B. Dihydromethysticin shows relatively high systemic exposure and fast
absorption in humans after oral kava intake, indicating it is one of the major active kavalactones contributing to kava's effects. ==References==