Schisandra chinensis has been widely used as a traditional herbal medicine to treat
chronic coughs,
fatigue, night sweats, and
insomnia. Numerous bioactive components including
lignans have been identified in this plant.
Lignans with a
dibenzocyclooctadiene moiety have been known to possess anti-
cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some
lignans to modulate some
cytochrome P450 (
P450) enzymes. Herein, we investigated the drug interaction potential of six
dibenzocyclooctadiene lignans (
schisandrin,
gomisin A, B, C, and N, and
wuweizisu C) on nine
P450 enzymes (
CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six
uridine 5'-diphosphoglucuronosyl
transferase (UGT)
enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that
lignans with one or two methylenedioxyphenyl groups inhibited
CYP2B6,
CYP2C8,
CYP2C9,
CYP2C19, and
CYP2E1 activities in a time- and concentration-dependent like their
CYP3A inhibition. In comparison, these
lignans do not induce time-dependent inhibition of
CYP1A2, CYP2A6, and
CYP2D6. The time-dependent inhibition of
gomisin A against
CYP2C8,
CYP2C19, and
CYP3A4 was also elucidated using
glutathione as a trapping
reagent of reactive
carbene metabolites given that
gomisin A strongly inhibits these
P450 enzymes in a time-dependent manner. A
glutathione conjugate of
gomisin A was generated in reactions with human recombinant
CYP2C8,
CYP2C19, and
CYP3A4. This suggests that the time-dependent inhibition of
gomisin A against
CYP2C8,
CYP2C9, and
CYP3A4 is due to the production of
carbene reactive metabolite. Six of the
lignans we tested inhibited the activities of six UGT to a limited extent (IC50 > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra
lignans and any co-administered drugs which are mainly metabolized by P450s.