Effects of kava (Kava-kava, 'Awa, Yaqona, Piper methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes.
The effects of the herbal product kava (Kava kava, 'Awa, Yaqona, Piper methysticum) on human P450 isoforms were studied in vitro using both cDNA-expressed human enzymes and cryopreserved human hepatocytes. Increasing concentrations of an ethanolic extract of dried kava root and three purified kava lactones (methysticin, desmethoxyyangonin, and yangonin) were tested for their ability to inhibit the catalytic activity of a panel of P450 isoforms (1A2, 2A6, 2C9, C2C19, 2D6, 2E1, and 3A4) present as c-DNA expressed-enzymes and in previously cryopreserved human hepatocytes. In addition, the test compounds' effect on hepatocyte viability was evaluated by measuring cellular ATP content. In both models, the kava extract and the three kava lactones were found to be potent inhibitors of CYPs 1A2, 2C9, 2C19, 2E1, and 3A4 with IC50 values of approximately 10 microM. The test compounds were also moderately cytotoxic to human hepatocytes (EC50 values of approximately 50 microM). Methysticin was the most potent enzyme inhibitor as well as the most cytotoxic, followed by (in order of potency:) the kava root extract, desmethoxyyangonin, and yangonin. Our results suggest that the drug interaction and hepatotoxic potential of kava should be further investigated.
Zou
L
L
Department of Medical Pharmacology and Toxicology, School of Medicine, University of California, Davis, CA 95616, USA.
Henderson
G L
GL
Harkey
M R
MR
Sakai
Y
Y
Li
A
A
D015925:Cryopreservation; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D020901:Kava; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018517:Plant Roots; D011714:Pyrans / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D011714:Pyrans; D011753:Pyrones; D003577:Cytochrome P-450 Enzyme System; C076881:methysticin; C110481:yangonin