Mechanism-Based Inhibition of Human Cytochrome P450 1A1 by Rhapontigenin

• Published in: Drug metabolism and disposition 2001-04, Vol.29 (4), p.389-393
• Main Authors: Chun, Young Jin, Ryu, Shi Yong, Jeong, Tae Cheon, Kim, Mie Young
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Enzyme Inhibitors - pharmacology; General pharmacology; Humans; In Vitro Techniques; Kinetics; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; NADP - metabolism; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Stilbenes - pharmacology
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.29.4.389

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 μM. 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 Kiand kinactivation were 0.09 μM 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.