Inhibition of Human Cytochrome P450 Activities by Kava Extract and Kavalactones

Abstract

The herb kava has recently been associated with numerous drug interactions, but its interaction with cytochrome P450 (P450) enzymes has not been investigated. In the present work the inhibition of P450 enzymes by kava extract and individual kavalactones in human liver microsomes (HLMs) was investigated. Whole kava extract (normalized to 100 microM total kavalactones) caused concentration-dependent decreases in P450 activities, with significant inhibition of the activities of CYP1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%) following preincubation for 15 min with HLMs and NADPH; CYP2A6, 2C8, and 2E1 activities were unaffected. The activities of CYP2C9, 2C19, 2D6, and 3A4 were also measured after incubation of HLMs with the major kavalactones kawain (K), desmethoxyyangonin (DMY), methysticin (M), dihydromethysticin (DHM) (each at 10 microM), and NADPH. Whereas K did not inhibit these enzymes, there was significant inhibition of CYP2C9 by DMY (42%), M (58%), and DHM (69%); of 2C19 by DHM (76%); of 2D6 by M (44%); and of 3A4 by DMY (40%), M (27%), and DHM (54%). Consistent with their potency as inhibitors, the two major kavalactones bearing a methylenedioxyphenyl moiety (M and DHM) formed "455 nm" metabolic intermediate complexes after incubation with HLMs and NADPH, but K and DMY did not. These data indicate that kava has a high potential for causing drug interactions through inhibition of P450 enzymes responsible for the majority of the metabolism of pharmaceutical agents.

Toxicity of Kava Kava

“…The total hepatic P450 content increased 35%, and activities of P450 enzymes increased significantly: CYP1A2 (4200%), 2B1 (4200%), and 3A1/2 (51%). The activity of CYP2E1 was marginally increased, and activity of CYP2D1 was modestly decreased by approximately 25% (77). The results between Mathews et al (77) and Clayton et al (82) are similar, although the latter found that the expression of hepatic CYP2E1 was changed.…”

“…Inhibition of CYP450 enzymes by whole kava extract and individual kavalactones (desmethoxyyangonin, dihydrokawain, dihydromethysticin, kawain, methysticin, and yangonin) was investigated in human liver microsomes (77). The extract caused significant inhibition of the activity of CYP1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11.…”

“…These results suggest that the kavalactone components, rather than other components of the extract, are responsible for the inhibition of CYP450 isozymes. Inhibition of CYP450 isozymes is believed to be the most likely factor in causing kava-mediated adverse drug reactions via inhibition of drug metabolism (77,78).…”

In vitro inhibition of cytochrome P-450 activities and quantification of constituents in a selection of commercial Rhodiola rosea products

“…[Ginkgoaceae] and grapefruit juice, among others, have already been identified as inhibiting agents towards CYP activities (Mathews et al 2002;Hanley et al 2011). Mathews et al (2002) showed that Kava extracts normalized to 10 lM total kavalactones inhibited in vitro CYP3A4, CYP1A2 and CYP2D6 activities with 42%, 36% and 22% of control, respectively.…”

Pregnane X receptor and natural products: beyond drug–drug interactions

“…Besides the well-documented effects on the CNS, kavalactones have been shown to modulate the activities of hepatic CYP enzymes. The activities of CYP1A2, -2C9, -2C19, -2D6 and -3A4 are inhibited by kavalactones through a competitive mechanism [43,44]. Interestingly, kava extracts have been found to induce the expression of the CYP3A4 gene, whereas kavalactones repress CYP3A4 enzymatic activity [45].…”