PT - JOURNAL ARTICLE AU - Hiroshi Iwata AU - Yasuhiro Tezuka AU - Shigetoshi Kadota AU - Akira Hiratsuka AU - Tadashi Watabe TI - IDENTIFICATION AND CHARACTERIZATION OF POTENT CYP3A4 INHIBITORS IN SCHISANDRA FRUIT EXTRACT AID - 10.1124/dmd.104.000646 DP - 2004 Dec 01 TA - Drug Metabolism and Disposition PG - 1351--1358 VI - 32 IP - 12 4099 - http://dmd.aspetjournals.org/content/32/12/1351.short 4100 - http://dmd.aspetjournals.org/content/32/12/1351.full SO - Drug Metab Dispos2004 Dec 01; 32 AB - Schisandra fruit, a Schisandraceae family herb, is used as a component in Kampo medicines (developed from Chinese medicines, but established in Japan). It can act as a sedative and antitussive, improve hepatic function, and give a general tonic effect. An extract of Schisandra fruit has been shown with a potent inhibitory effect on human liver microsomal erythromycin N-demethylation activity mediated by cytochrome P450 3A4 (CYP3A4). The present study was conducted to identify Schisandra fruit components having inhibitory effects on CYP3A4 by surveying the effect on human liver microsomal erythromycin N-demethylation activity. Known components of Schisandra fruit, gomisins B, C, G, and N and γ-shizandrin, showed inhibitory effects on N-demethylation activity. Among these components, gomisin C displayed the most potent and competitive inhibitory effect, with a Ki value of 0.049 μM. Furthermore, the inhibitory effect of gomisin C was stronger than that of ketoconazole (Ki = 0.070 μM), a known potent CYP3A4 inhibitor. Gomisin C, however, inhibited CYP1A2-, CYP2C9-, CYP2C19-, and CYP2D6-dependent activities only to a limited extent (IC50 values >10 μM). Moreover, gomisin C inactivated human liver microsomal erythromycin N-demethylation activity in a time- and concentration-dependent manner. The inactivation kinetic parameters kinact and KI were 0.092 min-1 and 0.399 μM, respectively. The human liver microsomal erythromycin N-demethylation activity inactivated by gomisin C did not recover on dialysis of the microsomes. Spectral scanning of CYP3A4 with gomisin C yielded an absorbance at 455 nm, suggesting that gomisin C inactivated the cytochrome P450 via the formation of a metabolite intermediate complex. This pattern is consistent with the metabolism of the methylenedioxy substituent in gomisin C. These results indicate that gomisin C is a mechanism-based inhibitor that not only competitively inhibits but irreversibly inactivates CYP3A4. The American Society for Pharmacology and Experimental Therapeutics