Characterization of Mouse Cytochrome P450-catalyzed Oxidative Metabolism of Rutaecarpine, an Alkaloid in the Herbal Medicine Evodia rutaecarpa
Woan-Ching Jan1,2,3, Ming-Jaw Don1, Li-Kang Ho2, Chieh-Fu Chen1 and Yune-Fang Ueng1,2,4*
1. National Research Institute of Chinese Medicine, 155-1, Sec. 2, Li-Nong St., Taipei 112, Taiwan, R.O.C.
2. Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
3. Mackay Medicine, Nursing and Management College, Taipei, Taiwan, R.O.C.
4. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan, R.O.C.
(Received: October 17, 2005; Accepted: December 21, 2005)
Abstract
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 Vmax values ranging, respectively, between 11.6~16.7 μM and 62~197 pmol/min/mg protein. The formation rates of the four hydroxylated metabolites were inhibited by α-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-, 11-, 12-, and 3-hydroxylation activities. Dexamethasone had no effect on these hydroxylation reactions in mice. These results indicated that CYP1A and CYP2B, but not CYP3A, play major roles in rutaecarpine hydroxylations in mice.
Abbreviations: CYP, cytochrome P450; 3-MC, 3-methylcholanthrene; G6P, glucose-6-phosphate; α-NF, α-naphthoflavone; β-NADP+, β-nicotinamide adenine dinucleotide phosphate.
Key words: rutaecarpine hydroxylation, cytochrome P450, mice, liver