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Concept: Bergamottin


Extracts, subfractions, isolated anthocyanins and procyanidins, and two phenolic acids from aronia [Aronia melanocarpa] were investigated for their CYP3A4 inhibitory effects, using midazolam as the probe substrate and recombinant insect cell microsomes expressing CYP3A4 as the enzyme source. Procyanidin B5 was a considerably stronger CYP3A4 inhibitor in vitro than the isomeric procyanidin B2 and comparable to bergamottin, a known CYP3A4 inhibitor from grapefruit juice. The inhibitory activity of proanthocyanidin-containing fractions was correlated to the degree of polymerization. Among the anthocyanins, cyanidin 3-arabinoside showed stronger CYP3A4 inhibition than cyanidin 3-galactoside and cyanidin 3-glucoside. Thus, the ability to inhibit CYP3A4 in vitro seems to be influenced by the sugar unit linked to the anthocyanidin.

Concepts: Cytochrome P450, Enzyme inhibitor, CYP3A4, Grapefruit, Grapefruit juice, Proanthocyanidins, B type proanthocyanidin, Bergamottin


The aim of the present study was to explore the effect of bergamottin, a natural furanocoumarin obtained from grapefruit juice, on the invasiveness of human glioma cells. The results revealed that treatment with bergamottin for 48 h significantly inhibited wound-healing migration and Matrigel invasion of human glioma cells, compared with untreated cells (P<0.05). Bergamottin treatment caused a significant decrease in the expression and secretion of matrix metalloproteinase (MMP)-9 in glioma cells compared with untreated cells (P<0.05). A Rac1-GTP pull-down assay demonstrated that bergamottin-treated glioma cells had a significantly decreased level of active Rac1-GTP compared with untreated cells (P<0.05). However, bergamottin had no significant effect on cell division cycle 42 activity. Expression of constitutively activated Rac1 almost completely restored the migration and invasion of bergamottin-treated glioma cells. In addition, bergamottin-induced downregulation of MMP-9 was prevented by exogenous activated Rac1. The results of the present study demonstrated that bergamottin exhibits anti-invasive activity in human glioma cells through the inactivation of Rac1 and downregulation of MMP-9.

Concepts: Cell nucleus, Cell, Cell division, Chromosome, Cell cycle, Matrix metalloproteinase, Grapefruit, Bergamottin


Furanocoumarins, such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB), isolated from grapefruit juice are clinically active constituents capable of inhibiting cytochrome P450 3A4. Furanocoumarins are also found in hassaku, pummelo and daidai. Several types of hybrid citrus fruits have recently been developed, and these may also contain furanocoumarins because they were produced by cross-breeding pummelo, daidai and other citrus fruits. In this study, we quantified BG and DHB levels in the flesh and peel of hybrid citrus fruits.

Concepts: Citrus, Cytochrome P450, Fruit, Orange, CYP3A4, Grapefruit, Tangelo, Bergamottin


Furocoumarins are a class of photoactive compounds found in several plant species, and may be responsible for the observed association between consumption of citrus products and the risk of skin cancer. Furocoumarin contents of several foods have been reported previously, but no comprehensive database of furocoumarin content of foods is currently available. Therefore, this study aimed to determine the distribution of furocoumarins in popularly consumed foods in the U.S. Samples of three varieties of each of 29 foods known or suspected to contain furocoumarins were purchased, prepared for analysis using a solid phase extraction method, and analyzed using UPLC-MS/MS for the presence of seven major furocoumarins. Most foods measured contained more than one furocoumarin, and some contained all seven of the furocoumarins examined. Total furocoumarin concentration was greatest in fresh parsley (23215 ng/g), grapefruits (21858 ng/g), lime juice (14580 ng/g), grapefruit juice (95341 ng/g), and limes (9151 ng/g). Bergamottin was found in the greatest proportion of foods sampled (23 of 29), followed by bergapten (19 of 29) and 6'7'-dihydroxybergamottin (16 of 29). These measurements will enable more accurate estimation of dietary furocoumarin exposure, and will strengthen future epidemiological work investigating the relationships between furocoumarin intake and health outcomes.

Concepts: Measurement, Citrus, Grapefruit, Rutaceae, Bergamottin, Furanocoumarin, Grapefruit spoon, Furanocoumarins


Furocoumarins are a class of organic compounds found in a variety of vegetables and fruits. Relatively little is known about the absorption and excretion of these compounds following ingestion. The objective of this study was to identify furocoumarins in grapefruit and grapefruit juice, and observe their kinetics in blood and urine. The furocoumarins detected in grapefruit using UPLC-MS/MS were bergamottin, 6',7'-dihydroxybergamottin (6',7'-DHB), epoxybergamottin, and bergaptol. Bergamottin, 6',7'-DHB, bergaptol, and bergapten were detected in grapefruit juice. In this study of 6 males and 3 females, only bergamottin and 6',7'-DHB were detected in plasma, whereas, in urine, four distinct furocoumarin metabolites as well as bergaptol, 6',7'-DHB, 8-methoxypsoralen (8-MOP), bergamottin, and psoralen were identified. Following grapefruit ingestion, furocoumarins were detectable in plasma as early as 15 minutes, and in urine within one hour. They remained in plasma for up to 3 or more hours and in urine as late as 24 hours.

Concepts: Citrus, Fruit, Grapefruit, Grapefruit juice, Bergamottin, Furanocoumarin, Grapefruit spoon, Furanocoumarins


Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells and the probe substrate estrone 3-sulfate, IC50 s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6',7-dihydroxybergamottin), and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice juice. Nobiletin was the most potent (IC50 , 3.7 μM); 6',7-dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50 , 20-50 μM); and bergamottin and hesperidin were the least potent (IC50 , >300 μM) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions.

Concepts: Pharmacology, Drugs, Natural product, Grapefruit, Grapefruit juice, Flavanone, Bergamottin, Naringin


To develop a comprehensive analytical method for photoactive furanocoumarins, grapefruit (whole, flesh, peel and juice) was extracted using QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method. Seven furanocoumarins: bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6',7'-dihydroxybergamottin (6',7'-DHB), epoxybergamottin and bergamottin were determined in grapefruit using UPLC-MS/MS. The concentrations of furanocoumarins in the plasma and urine of six healthy young adults before and after ingestion of grapefruit or grapefruit juice were also determined. Recovery rates of furanocoumarins by QuEChERS method from matrix spike sample and laboratory calibrate sample were 125.7 ± 25.4% and 105.7 ± 6.3%, respectively. Bergamottin and 6',7'-DHB were predominant compounds in grapefruit flesh, juice and plasma, while bergaptol and 6',7'-DHB were major compounds detected in the urine. The results demonstrated that bergamottin and 6',7'-DHB were metabolized to bergaptol. Overall, the analytical methods developed in the present study can be applied to the analysis of various furanocoumarins in plant sources and biological samples.

Concepts: Present, Metabolism, Cytochrome P450, Grapefruit, Psoralen, Year of birth missing, Bergamottin, Furanocoumarins


Due to the furanocoumarin compounds in the fruit, the production and consumption of grapefruit have been affected in the past decades since the ‘grapefruit juice effect’ was declared. To provide elite germplasm and obtain knowledge for future citrus breeding programs, the contents of 4 furanocoumarin monomers (FCMs) in the juice sacs from 73 citrus germplasms were evaluated using ultra-performance liquid chromatography. 6',7'-Dihydroxybergamottin and bergamottin were dominant in all the tested grapefruits, while there were some pomelos with dominant epoxybergamottin, and some with dominant 6',7'-dihydroxybergamottin and bergamottin. The contents of FCMs were low or below detection in sweet oranges, mandarins, lemons and trifoliate oranges. The results also show that the dominant patterns of FCMs are genotype-related, and crossing and selection are effective approaches to alter FCM profiles in citrus breeding. Furthermore, the contribution of pomelo as a parent to grapefruit regarding their FCM profiles was discussed.

Concepts: Citrus, Fruit, Orange, Grapefruit, Rutaceae, Pomelo, Tangelo, Bergamottin


A cell-based assay to measure cytochrome P450 3A4 (CYP3A4) induction was developed to screen for potential CYP3A4 inducers. This 96-well format assay utilizes HepG2 cells transfected with a gene construct of CYP3A4 proximal promoter linked to green fluorescence protein (GFP) gene, and the expression of the GFP is then measured quantitatively. Bergamottin at 5 to 25 µmol/L produced low induction relative to the positive control. Both curcumin and lycopene were not found to affect the expression of GFP, suggesting no induction properties toward CYP3A4. Interestingly, resveratrol produced significant induction from 25 µmol/L onward, which was similar to omeprazole and may warrant further studies. In conclusion, the present study demonstrated that this cell-based assay can be used as a tool to evaluate the potential CYP3A4 induction properties of compounds. However, molecular docking data have not provided satisfactory pointers to differentiate between CYP3A4 inducers from noninducers or from inhibitors, more comprehensive molecular screening may be indicated.

Concepts: DNA, Gene, Gene expression, Molecular biology, Green fluorescent protein, Cytochrome P450, CYP3A4, Bergamottin


Furanocoumarin compound psoralen (PRN) is a major active ingredient found in herbaceous plants. PRN has been used for the treatment of various dermal diseases in China. We evaluated the inhibitory effect of PRN on cytochrome P450 2B6 (CYP2B6) and found that PRN induced a time-, concentration-, and NADPH-dependent inactivation of CYP2B6 with the values of KI and kinact being 110.2 μM and 0.200 min(-1), respectively. Ticlopidine, a CYP2B6 substrate, prevented the enzyme from the inactivation induced by PRN. Exogenous nucleophile glutathione (GSH) and catalase/superoxide dismutase showed limited protection of CYP2B6 from the inactivation. The estimated partition ratio of the inactivation was approximately 400. GSH trapping experiments indicates that an epoxide or/and γ-ketoenal intermediate was formed in microsomal incubations with PRN. In summary, PRN was characterized as a mechanism-based inactivator of CYP2B6.

Concepts: Metabolism, Cytochrome P450, Paracetamol, Cysteine, Microsome, Perennial plant, CYP2B6, Bergamottin