Potent CYP3A4 inhibitory constituents of Piper cubeba

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2005-01, Vol.68 (1), p.64-68
• Main Authors: Usia, T, Watabe, T, Kadota, S, Tezuka, Y
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; chemical structure; cytochrome P-450; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; enzyme inhibition; enzyme inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Fruit - chemistry; General pharmacology; Humans; Indonesia; Inhibitory Concentration 50; Ketoconazole - pharmacology; lignans; Lignans - chemistry; Lignans - isolation & purification; Lignans - pharmacology; Medical sciences; medicinal plants; Microsomes, Liver - drug effects; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Piper - chemistry; Piper cubeba; plant extracts; Plants, Medicinal - chemistry; sesquiterpenoids; spectral analysis; stereochemistry; Stereoisomerism
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np0401765

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).