Received for publication June 1, 2004.
Revised July 24, 2004.
Accepted for publication July 26, 2004.

Desmethoxyyangonin and dihydromethysticin are two major pharmacological kavalactones with marked activity on the induction of cytochrome P4503A23

Abstract

ABSTRACT Kava kava (Piper methysticum), an herbal remedy, is widely used for the treatment of mild to moderate cases of anxiety. The therapeutic activity is presumably achieved through multiple constituents called kavalactones. Recently, kava extracts were shown to induce cytochrome P4503A4 (CYP3A4) and activate human pregnane X receptor (PXR). This study was undertaken to test the ability of purified kavalactones to induce CYP3A23 and activate PXR. Rat hepatocytes were treated with desmethoxyyangonin, dihydrokawain, dihydromethysticin, kawain, methysticin or yangonin, and the expression of CYP3A23 was monitored. Among the kavalactones, only desmethoxyyangonin and dihydromethysticin markedly induced the expression of CYP3A23 (~7 fold). Similar magnitude of induction was detected with combined six kavalactones at a non-inductive concentration when individually used. The induced expression, however, was markedly reduced or completely abolished if dihydromethysticin, desmethoxyyangonin or both were excluded from the mixtures. Interestingly, no matter if dihydromethysticin or desmethoxyyangonin was used alone or together with other kavalactones, similar amounts of total kavalactones were needed to produce comparable induction, suggesting that the inductive activity of dihydromethysticin and desmethoxyyangonin is additively/synergistically enhanced by other kavalactones. In addition, treatment with dihydromethysticin, desmethoxyyangonin or pregnenolone 16-carbonitrile (PCN) markedly increased the levels of CYP3A23 mRNA, and inhibition of mRNA synthesis abolished the induction. In contrast to PCN, dihydromethysticin and desmethoxyyangonin only slightly activated rat or human PXR. These findings suggest that induction of CYP3A23 by dihydromethysticin and desmethoxyyangonin involves transcription activation, probably through a PXR independent or a PXR-involved indirect mechanism.

Key words: CYP induction, CYP3A, cytochrome P450 regulation, drug-drug interactions, enzyme induction, induction, PXR

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