Characterization of Mouse Cytochrome P450-Catalyzed Oxidative Metabolism of Rutaecarpine, an Alkaloid in the Herbal Medicine Evodia Rutaecarpa

The alkaloid rutaecarpine exhibits antithrombotic and vasorelaxant effects. To characterize mouse cytochrome P450 (P450, CYP)-catalyzed rutaecarpine hydroxylations, the induction. inhibition, and kinetic properties of rutaecarpine hydroxylations were determined using liver microsomes of C57BL/6J mice. In untreated mice, rutaecarpine 10-, 11- 12-, and 3-hydroxylation had Km and V-max values ranging, respectively, between 11.6-16.7 mu M and 62 similar to 197 pmol/min/mg protein. The formation rates of the four hydroxylated metabolites were inhibited by a-naphthoflavone and orphenadrine. but not by either sulfaphenazole or ketoconazole. 3 -Methylcholanthrene- treatment increased rutaecarpine 11-, 12-, and 3-hydroxylation activities. Phenobarbital-treatment increased rutaecarpine 10-, ll-, 12-, and 3-hydroxylation activities. Dexamethasone had no effect on these hydroxylation reactions in mice. These results indicated that CYP1A and CYP213, but not CYP3A, play major roles in rutaccarpine hydroxylations in mice.Abbreviations: CYP, cytochrome P450, 3-MC, 3-methylcholanthrene: G6P, glucose-6-phosphate. alpha-NF, alpha-naphthoflavone; NADP+, beta-nicotinamide adenine dinucleotide phosphate.