Paradisin C: a new CYP3A4 inhibitor from grapefruit juice

Ohta, Tomihisa; Maruyama, Takuro; Nagahashi, Minoru; Miyamoto, Yasuyo; Hosoi, Shinzo; Kiuchi, Fumiyuki; Yamazoe, Yasushi; Tsukamoto, Sachiko

doi:10.1016/s0040-4020(02)00739-1

Cited by 55 publications

(48 citation statements)

References 11 publications

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“…In the course of our study on CYP inhibitors from foods, we have reported the isolation and structure elucidation of CYP inhibitors from grapefruit (Citrus paradisii) juice, [4][5][6] white pepper, Piper nigrum, 7,8) strawberry fruit, Fragaria ananassa, 9) and the commercially available black cohosh, Cimicifuga racemosa. 10) Licorice is prescribed in many Chinese traditional medicines and has been reported to contain flavonoids and triterpenoids.…”

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CYP3A4 Inhibitors Isolated from Licorice

Tsukamoto

Aburatani

Yoshida

et al. 2005

Biological & Pharmaceutical Bulletin

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Cytochrome P450 (CYP) enzymes are responsible for metabolism of a wide range of endogeneous compounds and xenobiotics, e.g. drug molecules, pollutants, and environmental compounds. Among members of the CYP enzyme family, CYP3A4 is the most abundant enzyme in human liver microsomes and intestinal epithelium; approximately 30% of the total CYP was suggested to be CYP3A4, 1) and more than 50% of clinically used drugs are oxidized by CYP3A4.2,3) It is well known that concomitant oral administration of several foods and herbs affects drug metabolism in humans by inhibiting CYP3A4 activity. In the course of our study on CYP inhibitors from foods, we have reported the isolation and structure elucidation of CYP inhibitors from grapefruit (Citrus paradisii) juice, [4][5][6] white pepper, Piper nigrum, 7,8) strawberry fruit, Fragaria ananassa, 9) and the commercially available black cohosh, Cimicifuga racemosa. 10) Licorice is prescribed in many Chinese traditional medicines and has been reported to contain flavonoids and triterpenoids. [11][12][13][14][15][16][17][18][19] Recently, we found that the extract of licorice (Glycyrrhiza uralensis FISHER, Leguminosae) showed potent CYP3A4 inhibitory activity with the IC 50 value of 0.022 mg/ml. This paper reports the isolation, structure identification, and CYP inhibitory activity of the constituents of licorice. MATERIALS AND METHODS General ProceduresOptical rotations were determined with a Horiba SEPA-300 high sensitive polarimeter. NMR spectra were recorded on a JEOL GSX500 NMR spectrometer. Mass spectra were measured on a JEOL SX-102 mass spectrometer.Plant Materials The rhizomes of G. uralensis were purchased from Tochimoto Co., Ltd. (Osaka, Japan). A voucher specimen is deposited in the Laboratory of Pharmacognosy and Chemistry of Natural Products, Graduate School of Natural Science and Technology, Kanazawa University, Japan.Isolation of Compounds 1-9 The rhizomes (0.5 kg) of G. uralensis were extracted with methanol (MeOH) (3 lϫ3) at room temperature. The extract was evaporated in vacuo, and the residue was partitioned between ethyl acetate (EtOAc) and water (H 2 O). The aqueous fraction was then partitioned between butanol (BuOH) and water. The EtOAc soluble fraction (34.7 g) was subjected to column chromatography on silica gel with hexane/EtOAc followed by ODS column chromatography with MeOH/H 2 O to afford 1-4 (Fig. 1). The BuOH soluble fraction (34.9 g) was subjected to column chromatography on ODS with MeOH/H 2 O followed by ODS HPLC with MeOH/H 2 O to afford 6 and 8. The aqueous fraction (31.3 g) was subjected to column chromatography on ODS with MeOH/H 2 O followed by ODS HPLC with MeOH/H 2 O to afford 5, 7, and 9.Assay of CYP3A4 Inhibition CYP3A4 activity was measured based on nifedipine oxidation. Various amounts (0-10 mM, final concentration) of samples in 1 ml of dimethylsulfoxide (DMSO) were added to 192 ml of 100 mM phosphate buffer (pH 7.4) containing 50 mM nifedipine (Wako Pure Chemical Industries, Ltd., Osaka, Japan), 5 mM glucose-6-phosphate (Oriental...

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confidence: 99%

CYP3A4 Inhibitors Isolated from Licorice

Tsukamoto

Aburatani

Yoshida

et al. 2005

Biological & Pharmaceutical Bulletin

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“…According to previous studies (Fukuda, Guo, Ohashi, Yoshikawa, & Yamazoe, 2000;Guo & Yamazoe, 2004;Manthey & Buslig, 2005;Ohta et al, 2002), the typical [MþH] þ ions of already identified furanocoumarins by ESI were at m/z 203, 339, 355, 373, 709 and 727. They correspond to bergaptol, bergamottin, 6 0 ,7 0 -epoxybergamottin and 6 0 ,7 0 -dihydroxybergamottin, paradisin B and paradisin A and C, respectively.…”

Section: Identification Of Furanocoumarinsmentioning

confidence: 81%

New furanocoumarins detected from grapefruit juice retentate

Buslig

Haun

et al. 2009

Natural Product Research

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Grapefruit (Citrus paradisi Macf.) furanocoumarins and related compounds have been shown to interact with the enterocyte cytochrome P450, CYP3A4, and as a result they affect the bioavailibility of certain drugs. Only a few grapefruit furanocoumarins have been identified so far. In this study, grapefruit juice retentate, rich in furanocoumarins, was extracted and then separated by flash chromatography for the examination of new compounds. Finally, nine new furanocoumarins were detected in different fractions according to their UV spectra and mass spectrometric properties by LC-MS (liquid chromatography mass spectrometry) and tentatively designated as FC 338, FC 420, FC 524, FC 530, FC 540, FC 546, FC 552, FC 570 and FC 614.

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“…Ohta et al 25 detail the isolation and identification of a new natural compound, paradisin C (9.10). The elucidation was based on high-resolution FAB-MS data which gave a molecular formula of C 42 H 46 O 11 and using 2D NMR spectra HMQC, COSY (10), and HMBC (63).…”

Section: Paradisin Cmentioning

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Approaches to Algorithmic Structure Elucidation

2011

Contemporary Computer-Assisted Approaches to Molecular Structure Elucidation

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In this chapter we will provide an overview of the capabilities of the second generation StrucEluc system that is capable of elucidating the chemical structures of larger molecules up to a mass of 1500 amu and containing more than 100 skeletal atoms. This platform requires 13C and 1H NMR spectra in combination with homonuclear and heteronuclear 2D NMR correlations and does not require any additional structural information to create connectivities from the spectral data and generate all possible structures satisfying the molecular formula of the unknown. The chapter will be developed around a flowchart describing the structure elucidation process and will break down the entire process into six specific sections: (1) the operation of the system with 1D NMR spectra, (2) the so-called “Common” 2D NMR mode, (3) the application of fragments in combination with 2D NMR data, (4) the selection of the most probable structure, (5) the imposition of additional constraints and (6) the utilization of fragments present in a knowledgebase of spectral data. Each of these sections will be discussed in detail.

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Paradisin C: a new CYP3A4 inhibitor from grapefruit juice

Cited by 55 publications

References 11 publications

CYP3A4 Inhibitors Isolated from Licorice

CYP3A4 Inhibitors Isolated from Licorice

New furanocoumarins detected from grapefruit juice retentate

Approaches to Algorithmic Structure Elucidation

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