Recently we reported that
resveratrol (trans-3,4',5-trihydroxystilbene) showed selective inhibition of recombinant human
cytochrome P450 (P450) 1A1 in a concentration-dependent manner. The inhibition of recombinant human P450 1A1, 1A2, or 1B1 by various hydroxystilbene compounds having a similar structure to
resveratrol was investigated using bacterial membranes from a human P450/
NADPH-P450 reductase bicistronic expression system to find new candidates for
cancer chemopreventive agents. Of seven compounds tested,
rhapontigenin (3,3',5-trihydroxy-4'-methoxystilbene) exhibited a potent and selective inhibition of human P450 1A1 with an IC50 value of 0.4 microM.
Rhapontigenin showed 400-fold selectivity for P450 1A1 over P450 1A2 and 23-fold selectivity for P450 1A1 over P450 1B1.
Rhapontigenin did not show any significant inhibition of
ethoxyresorufin O-deethylation (
EROD) activity in human liver microsomes, the other human P450s such as P450 2E1, P450 3A4, P450 2D6, P450 2C8, and P450 2C9, or human
NADPH-P450 reductase. We have further investigated the inhibition kinetics of P450 1A1 by
rhapontigenin.
Rhapontigenin inhibited
EROD activity of expressed human P450 1A1 in a competitive manner. The loss of
EROD activity was time- and concentration-dependent. The values for K(i) and k(inactivation) were 0.09 microM and 0.06 min(-1), respectively. The loss was not blocked by the trapping agents
glutathione,
N-acetylcysteine, or
dithiothreitol. These results suggest that
rhapontigenin is a potent mechanism-based inactivator of human P450 1A1 and may be considered as a good candidate for a
cancer chemopreventive agent in humans.