PT - JOURNAL ARTICLE AU - Yuzhong Ma AU - Karuna Sachdeva AU - Jirong Liu AU - Michael Ford AU - Dongfang Yang AU - Ikhlas A. Khan AU - Clinton O. Chichester AU - Bingfang Yan TI - DESMETHOXYYANGONIN AND DIHYDROMETHYSTICIN ARE TWO MAJOR PHARMACOLOGICAL KAVALACTONES WITH MARKED ACTIVITY ON THE INDUCTION OF CYP3A23 AID - 10.1124/dmd.104.000786 DP - 2004 Nov 01 TA - Drug Metabolism and Disposition PG - 1317--1324 VI - 32 IP - 11 4099 - http://dmd.aspetjournals.org/content/32/11/1317.short 4100 - http://dmd.aspetjournals.org/content/32/11/1317.full SO - Drug Metab Dispos2004 Nov 01; 32 AB - 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 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). A similar magnitude of induction was detected with combined six kavalactones at a noninductive 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, regardless of whether 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 16α-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 the induction of CYP3A23 by dihydromethysticin and desmethoxyyangonin involves transcription activation, probably through a PXR-independent or PXR-involved indirect mechanism. The American Society for Pharmacology and Experimental Therapeutics