Selective inhibition of human cytochrome p450 1a1 by 3, 3',4', 5, 5'-pentamethoxystilbene

SK Leea, SS Parka, S Kim, PhDb, MY Kim, PhDa, YJ Chun, PhDa

a College of Pharmacy, Chungang University, Seoul 156-756 b Natural Products Research Institute, Seoul National University, Seoul 110-460

Recently we have suggested that various hydroxystilbene compounds from medicinal plants showed strong inhibition of activities of human P450 1 isozymes such as CYP1A1, 1A2, and 1B1. Here we reported that 3,3',4',5,5'-pentamethoxystilbene (PMS), a synthetic stilbene compound, exhibited a potent and selective inhibition of human CYP1A1 with an IC50 value of 0.14 µM. PMS showed 6700-fold greater selective inhibition of CYP1A1 over CYP1A2 (IC50=934 µM) and 23-fold selectivity for CYP1A1 over CYP1B1 (IC50=3.2 µM). PMS did not show any significant inhibition of ethoxyresorufin O-deethylation (EROD) activity in human liver microsomes. To elucidate the mechanism of inhibition by PMS, kinetic studies were performed. Analysis of the mode of inhibition indicated mixed-type inhibition of CYP1A1. The inhibition by PMS was not mechanism-based and blocked by trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol. To investigate the inhibitory mechanism of PMS in cells, the effects of PMS on dioxin-induced EROD activity were studied in human hepatoma HepG2 cells. PMS significantly suppressed CYP1A1-dependent EROD activity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Taken together, PMS is one of the selective inhibitor of human CYP1A1 and may be considered as a good candidate for a cancer preventive agent in human.

KEY WORDS: 8-tetrachlorodibenzo-p-dioxin (TCDD), Stilbene.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prevention.