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The EtOAc-soluble fraction of the water extract of Piper cubeba, having shown potent inhibitory activity on the metabolism mediated by CYP3A4, was subjected to activity-guided isolation to yield two new lignans, (8R,8'R)-4-hydroxycubebinone (1) and (8R,8'R,9'S)-5-methoxyclusin (2), and two new sesquiterpenes, (5 alpha,8 alpha)-2-oxo-1(10),3,7(11)-guaiatrien-12,8-olide (3) and (1 alpha,2 beta,5 alpha,8 alpha 10 alpha)-1,10-epoxy-2-hydroxy-3,7(11)-guaiadien-12,8-olide (4), along with 16 known compounds (5-20). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. The compounds (8R,8'R,9'S)-5-methoxyclusin (2), (-)-clusin (10), (-)-yatein (13), ethoxyclusin (15), and (-)-dihydroclusin (17), having one methylenedioxyphenyl moiety in their structures, showed very potent and selective inhibitory activity against CYP3A4 with IC(50) values (0.44-1.0 microM) identical to that of the positive control, ketoconazole (IC(50), 0.72 microM).

Herbal medicines are used concomitantly with conventional prescription drugs, which is a situation that carries the risk of unanticipated adverse drug-herbal pharmacokinetic interactions. It is recognized that cytochrome P450 (CYP) enzyme inactivation is one of the main reasons for pharmacokinetic interactions.1,2) The inactivation of CYP can lead to serious clinical drug interactions, especially when concomitant drugs are metabolized by the same enzyme. The drug interactions cause symptoms of drug overdose, including an exaggerated pharmacological response and/or drug toxicity. 3)One of the mechanism of CYP inactivation involves covalent binding of a reactive intermediate to the enzyme proteins and/or heme, which leads to irreversible inhibition of catalytic function, or a quasi-irreversible coordination of a reactive intermediate to the CYP. 4) In Indonesia, herbal medicines "Jamu" have been used from ancient times until the present, and are consumed by people of different levels. Most of these herbal medicines are unregulated, and many patients do not inform their physician of the herbal medicines they consume. Therefore, interactions between herbal medicines and drugs prescribed clinically are becoming a concern. Thus, we investigated in vitro the cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) inhibitory activity of Indonesian medicinal plants. We found that MeOH extracts of Zingiber aromaticum (IC 50 , 102 mg/ml) and Piper cubeba (IC 50 , 53 mg/ ml) showed potent inhibitory activity against CYP3A4, while the MeOH extract of Catharanthus roseus revealed very potent inhibition against CYP2D6 with an IC 50 value of 11 mg/ml.5) In addition, we reported the CYP3A4 and CYP2D6 inhibitory constituents of Z. aromaticum 6) and P. cubeba. 7)Catharanthus roseus, also known as Vinca rosea, is a semiwoody evergreen perennial tree that originated in Madagascar. It has been widely cultivated for hundreds of years and can now be found growing wild in most warm regions of the world. The plant has historically been used to treat a wide assortment of diseases. It was used as a folk remedy for diabetes in Europe for centuries, while in Hawai, the plant was boiled to make a poultice to stop bleeding. In China, it was used as an astringent, diuretic, and cough remedy, and in Central and South America it was used as a homemade cold remedy to ease lung congestion, inflammation, and sore throat. 8) In Indonesia, on the other hand, it was used for treatment of malaria, diabetes, constipation, cancer, and hypertension.9) More than 70 alkaloids were isolated from C. roseus, including vincristine and vinblastine which have anticancer properties.8) Because of continued interest in the CYP study, we carried out phytochemical investigation of C. roseus from Indonesia. In this paper, we report the constituents of this plant and their inhibitory activity on the metabolism mediated by CYP3A4 and CYP2D6. We also examined the possibility of mechanism-based inhibition by these constituents. MATERIALS AND METHODS Extraction and IsolationThe aerial...

Three new sesquiterpenes, (2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (1), (2R,3R,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (2), and (5R)-2,6,9-humulatrien-5-ol-8-one (3), and two new flavonol glycosides, kaempferol-3-O-(2,3-di-O-acetyl-alpha-l-rhamnopyranoside) (4) and kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5), were isolated from the EtOAc-soluble fraction of the water extract of Zingiber aromaticum, along with 13 known compounds (6-18). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5) showed the most potent inhibitory activity (IC(50), 14.4 microM) on the metabolism mediated by CYP3A4, and kaempferol-3-O-methyl ether (14) inhibited CYP2D6 most potently (IC(50), 4.63 microM).