PT - JOURNAL ARTICLE AU - Yune-Fang Ueng AU - Ming-Jaw Don AU - Woan-Ching Jan AU - Shu-Yun Wang AU - Li-Kang Ho AU - Chieh-Fu Chen TI - OXIDATIVE METABOLISM OF THE ALKALOID RUTAECARPINE BY HUMAN CYTOCHROME P450 AID - 10.1124/dmd.105.007849 DP - 2006 May 01 TA - Drug Metabolism and Disposition PG - 821--827 VI - 34 IP - 5 4099 - http://dmd.aspetjournals.org/content/34/5/821.short 4100 - http://dmd.aspetjournals.org/content/34/5/821.full SO - Drug Metab Dispos2006 May 01; 34 AB - Rutaecarpine is the main active alkaloid of the herbal medicine, Evodia rutaecarpa. To identify the major human cytochrome P450 (P450) participating in rutaecarpine oxidative metabolism, human liver microsomes and bacteria-expressed recombinant human P450 were studied. In liver microsomes, rutaecarpine was oxidized to 10-, 11-, 12-, and 3-hydroxyrutaecarpine. Microsomal 10- and 3-hydroxylation activities were strongly inhibited by ketoconazole. The 11- and 12-hydroxylation activities were inhibited by α-naphthoflavone, quinidine, and ketoconazole. These results indicated that multiple hepatic P450s including CYP1A2, CYP2D6, and CYP3A4 participate in rutaecarpine hydroxylations. Among recombinant P450s, CYP1A1 had the highest rutaecarpine hydroxylation activity. Decreased metabolite formation at high substrate concentration indicated that there was substrate inhibition of CYP1A1- and CYP1A2-catalyzed hydroxylations. CYP1A1-catalyzed rutaecarpine hydroxylations had Vmax values of 1388 to ∼1893 pmol/min/nmol P450, Km values of 4.1 to ∼9.5 μM, and Ki values of 45 to ∼103 μM. These results indicated that more than one molecule of rutaecarpine is accessible to the CYP1A active site. The major metabolite 10-hydroxyrutaecarpine decreased CYP1A1, CYP1A2, and CYP1B1 activities with respective IC50 values of 2.56 ± 0.04, 2.57 ± 0.11, and 0.09 ± 0.01 μM, suggesting that product inhibition might occur during rutaecarpine hydroxylation. The metabolite profile and kinetic properties of rutaecarpine hydroxylation by human P450s provide important information relevant to the clinical application of rutaecarpine and E. rutaecarpa. The American Society for Pharmacology and Experimental Therapeutics