Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities.
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).
Usia
Tepy
T
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630-Sugitani, Toyama 930-0194, Japan.
Iwata
Hiroshi
H
Hiratsuka
Akira
A
Watabe
Tadashi
T
Kadota
Shigetoshi
S
Tezuka
Yasuhiro
Y
D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D044948:Flavonols / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D007214:Indonesia; D044949:Kaempferols / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D008518:Medicine, East Asian Traditional; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010946:Plants, Medicinal / Q000737:chemistry*; D027343:Rhizome / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013237:Stereoisomerism; D030521:Zingiberaceae / Q000737:chemistry*
C488576:(2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one; C488577:(5R)-2,6,9-humulatrien-5-ol-8-one; D044948:Flavonols; D006027:Glycosides; D044949:Kaempferols; D012717:Sesquiterpenes; C488579:kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside); C488578:kaempferol-3-O-(2,3-di-O-acetyl-alpha-l-rhamnopyranoside); D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human