Epoxybergamottin

Intake of Furocoumarins and Risk of Skin Cancer in 2 Prospective US Cohort Studies.[Pubmed:32221600]

J Nutr. 2020 Jun 1;150(6):1535-1544.

BACKGROUND: In prior studies, higher citrus consumption was associated with higher risk of cutaneous malignant melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furocoumarins, compounds with phototoxicity and photocarcinogenicity in citrus, may be responsible for the association. OBJECTIVES: The objective of the study was to investigate the association between furocoumarin intake and skin cancer risk. METHODS: A total of 47,453 men from the Health Professionals Follow-Up Study (HPFS) and 75,291 women from the Nurses' Health Study (NHS) with diet data collected every 2-4 y in the 2 prospective cohort studies were included. A furocoumarin food composition database for 7 common furocoumarins [bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6',7'-dihydroxybergamottin (6'7'-DHB), Epoxybergamottin, and bergamottin] was developed and used to calculate participants' cumulative average and energy-adjusted furocoumarin intake. Multivariate HRs and 95% CIs of the associations between furocoumarin intake and skin cancer risk were estimated using Cox proportional hazards models. Analyses were performed separately in each cohort as well as pooled using a fixed-effects model. RESULTS: Throughout follow-up (1984-2012 in the NHS and 1986-2012 in the HPFS), we identified 1593 melanoma, 4066 SCC, and 28,630 BCC cases. Higher intake of total furocoumarins was associated with an increased risk of BCC; the pooled HR comparing the top with the bottom quintile was 1.16 (95% CI: 1.11, 1.21; P-trend = 0.002). Higher intakes of bergaptol, bergapten, 6'7'-DHB, and bergamottin were also significantly associated with increased BCC risk. No significant associations were found between intake of total furocoumarins and the risks of SCC or melanoma. CONCLUSIONS: Intakes of total furocoumarins as well as some individual furocoumarins were associated with an increased risk of skin cancer, especially BCC, in 2 cohorts of US health professionals.

Determination of citrus juice coumarins, furanocoumarins and methoxylated flavones using solid phase extraction and HPLC with photodiode array and fluorescence detection.[Pubmed:30236679]

Food Chem. 2019 Jan 15;271:29-38.

A synergistic combination of analytical techniques was developed for the simultaneous determination of the three most biologically active chemical families in citrus juices: methoxylated flavones, coumarins, and furanocoumarins. No rapid methodology has been available to determine them together. A solid phase extraction concentrated these groups and a ternary reverse phase HPLC gradient completely resolved them from other juice components. Two coumarins, isomeranzin and osthole, were identified in a sweet orange (C. sinensis) cultivar, Changyecheng, for the first time. Pummelo juice was characterized by coumarin and furanocoumarin epoxides such as meranzin and Epoxybergamottin. No epoxides were observed in the more acidic juices. Added furanocoumarin epoxides hydrolyzed rapidly in the most acidic juices. The ratios of the UV peak areas at 320nm to the fluorescence emission peaks as well as the ratio of fluorescence emission peaks at 450-400nm could be used to identify chromatographic peaks.

Chemistry and health effects of furanocoumarins in grapefruit.[Pubmed:28911545]

J Food Drug Anal. 2017 Jan;25(1):71-83.

Furanocoumarins are a specific group of secondary metabolites that commonly present in higher plants, such as citrus plants. The major furanocoumarins found in grapefruits (Citrus paradisi) include bergamottin, Epoxybergamottin, and 6',7'-dihydroxybergamottin. During biosynthesis of these furanocoumarins, coumarins undergo biochemical modifications corresponding to a prenylation reaction catalyzed by the cytochrome P450 enzymes with the subsequent formation of furan rings. Because of undesirable interactions with several medications, many studies have developed methods for grapefruit furanocoumarin quantification that include high-performance liquid chromatography coupled with UV detector or mass spectrometry. The distribution of furanocoumarins in grapefruits is affected by several environmental conditions, such as processing techniques, storage temperature, and packing materials. In the past few years, grapefruit furanocoumarins have been demonstrated to exhibit several biological activities including antioxidative, -inflammatory, and -cancer activities as well as bone health promotion both in vitro and in vivo. Notably, furanocoumarins potently exerted antiproliferative activities against cancer cell growth through modulation of several molecular pathways, such as regulation of the signal transducer and activator of transcription 3, nuclear factor-kappaB, phosphatidylinositol-3-kinase/AKT, and mitogen-activated protein kinase expression. Therefore, based on this review, we suggest furanocoumarins may serve as bioactive components that contribute, at least in part, to the health benefits of grapefruit.

Anti-Inflammatory and Neuroprotective Constituents from the Peels of Citrus grandis.[Pubmed:28598384]

Molecules. 2017 Jun 9;22(6). pii: molecules22060967.

A series of chromatographic separations performed on the ethanol extracts of the peels of Citrus grandis has led to the characterization of forty compounds, including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compounds, respectively. The chemical structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric analysis. Most of the isolated compounds were examined for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18-dihydroxybergamottin (12), Epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 muM, and 0.43 to 4.33 muM, respectively. In addition, 7-hydroxy-8-(2'-hydroxy-3'-methylbut-3'-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against A-mediated neurotoxicity at 50 muM.

Furocoumarin Kinetics in Plasma and Urine of Healthy Adults Following Consumption of Grapefruit (Citrus paradisi Macf.) and Grapefruit Juice.[Pubmed:28322044]

J Agric Food Chem. 2017 Apr 12;65(14):3006-3012.

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 min and in urine within 1 h. They remained in plasma for up to 3 or more hours and in urine as late as 24 h.

Development of a comprehensive analytical method for furanocoumarins in grapefruit and their metabolites in plasma and urine using UPLC-MS/MS: a preliminary study.[Pubmed:27396405]

Int J Food Sci Nutr. 2016 Dec;67(8):881-7.

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.

Content evaluation of 4 furanocoumarin monomers in various citrus germplasms.[Pubmed:25977000]

Food Chem. 2015 Nov 15;187:75-81.

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.

Multidimensional liquid chromatography for the determination of chiral coumarins and furocoumarins in Citrus essential oils.[Pubmed:22807365]

J Sep Sci. 2012 Jul;35(14):1828-36.

In this work the enantiomeric distribution of chiral coumarins (meranzin and epoxyaurapten), and furocoumarins (oxypeucedanin, byakangelicol, and Epoxybergamottin) in different Citrus essential oils (lemon, lime, grapefruit, and bitter orange) was determined by means of a heart-cutting multidimensional-liquid chromatography (MD-LC) system, equipped with a microsilica column in the first dimension in a combination to a cellulosic-based chiral column used in the second dimension. The normal phase-liquid chromatography-liquid chromatography (NP-LC-LC) instrumentation was equipped with a photodiode array detector and a multiport valve as interface. For method optimization and the determination of absolute configuration, natural compounds were isolated and racemic mixture was synthesized. The NP-LC-LC/PDA (where PDA is photodiode array) method provided a good baseline separation of chiral coumarins (meranzin and epoxyaurapten) and furocoumarins (Epoxybergamottin and byakangelicol) present in cold-pressed Citrus essential oils without any sample pretreatment. Results obtained showed that for all the chiral compounds present in Citrus essential oils analyzed, there is always a clear prevalence of one of the two enantiomers, and do not appear influenced by the different geographical origin of the oils.

Biotransformations of 6',7'-dihydroxybergamottin and 6',7'-epoxybergamottin by the citrus-pathogenic fungi diminish cytochrome P450 3A4 inhibitory activity.[Pubmed:22342630]

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2279-82.

Penicillium digitatum, as well as five other citrus pathogenic species, (Penicillium ulaiense Link, Geotrichum citri Link, Botrytis cinerea P. Micheli ex Pers., Lasiodiplodia theobromae (Pat.) Griffon & Maubl., and Phomopsis citri (teleomorph Diaporthe citri)) were observed to convert 6',7'-Epoxybergamottin (1) into 6',7'-dihydroxybergamottin (2), bergaptol (3), and an opened lactone ring metabolite 6,7-furano-5-(6',7'-dihydroxy geranyloxy)-2-hydroxy-hydrocoumaric acid (4). Metabolism of 2 by these fungi also proceeded to 4. The structure of 4 was established by high resolution mass spectrometry and (1)H and (13)C NMR techniques. The inhibitory activity of 4 towards human intestinal cytochrome P450 3A4 (CYP3A4) was greatly decreased (IC(50) >172.0 muM) compared to 2 (IC(50)=0.81 muM).

Flavonoid composition and antioxidant activity of juices from Chinotto ( Citrus x myrtifolia Raf.) fruits at different ripening stages.[Pubmed:20155909]

J Agric Food Chem. 2010 Mar 10;58(5):3031-6.

The qualitative and quantitative compositions of chinotto juice in two different maturation periods were determined via chromatographic separation of extracted aliquots of juice of Citrus x myrtifolia Raf. by using reverse-phase LC-DAD-ESI-MS-MS. This provides a comprehensive chromatographic evaluation of 11 compounds (furanocoumarins and flavonoids C- and O-glycosides). Five flavonoids and two furanocoumarins were identified for the first time in chinotto juice: two C-glucosides (vicenin-2 and lucenin-2 4'-methyl ether), two O-glycosides (narirutin and rhoifolin), and a 3-hydroxy-3-methylglutaryl flavanone (brutieridin). Bergapten and Epoxybergamottin were the primary furanocoumarins found. Overall, the juice from immature chinotto fruits is richer in bioactive compounds than that obtained from ripe fruits. The free radical and superoxide anion scavenging activities of juice from both green and ripe fruits were assessed, and results showed that the former is much more efficient in scavenging radical and superoxide species than the latter.

Isolation and identification of insecticidal components from Citrus aurantium fruit peel extract.[Pubmed:18578532]

J Agric Food Chem. 2008 Jul 23;56(14):5577-81.

Three active components were identified by bioassay-guided fractionation of bitter orange ( Citrus aurantium L.) fruit peel petroleum ether extract. Silica gel fractionation of the extract yielded a fraction that inflicted up to 96% mortality to adults of the olive fruit fly Bactrocera oleae (Gmelin) three days post-treatment. Subsequent HPLC purification of the active fraction resulted in the isolation of three components, eluted in fractions F 222, F 224, and F 226, that induced adult mortality. Considering the data obtained from UV, FTIR, MS, and (1)H NMR spectra, they were identified as 7-methoxy-8-(3'-methyl-2'-butenyl)-2 H-1-benzopyran-2-one (osthol), 4-methoxy-7 H-furo[3,2- g]benzopyran-7-one (bergapten), and 4-(( E)-3'-methyl-5'-(3'',3''-dimethyloxiran-2''-yl)pent-2'-enyloxy)-7 H-furo[3,2- g][1]benzopyran-7-one (6',7'-Epoxybergamottin). Our results are in concordance with those reported in the literature and were further verified by direct comparison to authentic components. 6',7'-Epoxybergamottin was toxic when tested individually, while bergapten and osthol were found to act synergistically to 6',7'-Epoxybergamottin.

Aspergillus niger metabolism of citrus furanocoumarin inhibitors of human cytochrome P450 3A4.[Pubmed:18183388]

Appl Microbiol Biotechnol. 2008 Feb;78(2):343-9.

Fungi metabolize polycyclic aromatic hydrocarbons by a number of detoxification processes, including the formation of sulfated and glycosidated conjugates. A class of aromatic compounds in grapefruit is the furanocoumarins (FCs), and their metabolism in humans is centrally involved in the "grapefruit/drug interactions." Thus far, the metabolism by fungi of the major FCs in grapefruit, including 6', 7'-Epoxybergamottin (EB), 6', 7'-dihydroxybergamottin (DHB), and bergamottin (BM), has received little attention. In this study, Aspergillus niger was observed to convert EB into DHB and a novel water-soluble metabolite (WSM). Bergaptol (BT) and BM were also metabolized by A. niger to the WSM, which was identified as BT-5-sulfate using mass spectrometry, UV spectroscopy, chemical hydrolysis, and (1)H and (13)C nuclear magnetic resonance spectroscopy. Similarly, the fungus had a capability of metabolizing xanthotoxol (XT), a structural isomer of BT, to a sulfated analog of BT-5-sulfate, presumably XT-8-sulfate. A possible enzyme-catalyzed pathway for the grapefruit FC metabolism involving the cleavage of the geranyl group and the addition of a sulfate group is proposed.

Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells.[Pubmed:17542018]

J Pharm Sci. 2007 Oct;96(10):2808-17.

To investigate the potential interaction between selected ingredients of grapefruit juice and, the transport of talinolol, a P-gp substrate, across Caco-2 cells monolayers was determined in the absence and presence of distinct concentrations of grapefruit juice, bergamottin, 6',7'-dihydroxybergamottin, 6',7'-Epoxybergamottin, naringin, and naringenin. Talinolol permeability was selectively inhibited by grapefruit juice and its components. The furano coumarin, 6',7'-Epoxybergamottin, was the most potent inhibitor (IC(50) = 0.7 microM), followed by 6',7'-dihydroxybergamottin (IC(50) = 34 microM) and bergamottin that did not show any inhibition at concentrations up to 10 microM. The flavonoid aglycone naringenin was around 10-fold more potent than its glycoside naringin with IC(50) values of 236 and 2409 microM, respectively. The flavonoids and furanocoumarins tested in this study are in the same range of concentration they are present in the juice contributing, therefore, for the overall inhibitory effect of GFJ on P-gp activity. The in vitro data suggest that compounds present in grapefruit juice are able to inhibit the P-gp activity modifying the disposition of drugs that are P-gp substrates such as talinolol.

Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4.[Pubmed:16604230]

Org Biomol Chem. 2006 Apr 21;4(8):1604-10.

A number of furanocoumarins isolated from grapefruit juice have been found to inhibit CYP3A4 activity in vitro. In this study, we have designed and synthesised a range of analogues based on bergamottin to investigate the relationship between chemical structure and inhibition of CYP3A4 activity. Studies were performed using human liver microsomes and human intestinal S9 fraction, with testosterone as the marker substrate. With the exception of the coumarin and phenolic furanocoumarin derivatives, which were inactive, the alkyloxy-furanocoumarin analogues were found to inhibit CYP3A4 activity in a dose dependent manner, with observed IC50 values ranging from 0.13 +/- 0.03 to 49.3 +/- 1.9 microM. The unsaturated furan derivatives were found to exhibit time-dependent inhibition, showing a 2-, 4- and 14-fold increase in potency for 6',7'-Epoxybergamottin, 6',7'-dihydroxybergamottin and bergamottin, respectively after a preincubation period of ten minutes. Reduction of the furan moiety resulted in an 11-fold decrease in inhibitory potency, suggesting that this functional group is key to the interaction between these compounds and CYP3A4.

Distribution of furanocoumarins in grapefruit juice fractions.[Pubmed:15969491]

J Agric Food Chem. 2005 Jun 29;53(13):5158-63.

The reported effects of grapefruit (Citrus paradisi Macf.) juice on oral bioavailability of certain prescription drugs have led to the discovery of the inhibition by compounds in grapefruit of cytochrome P450 3A4 (CYP3A4) in the intestinal wall and liver. Recent evidence indicates that furanocoumarins related to bergamottin [5-[(3',7'-dimethyl-2',6'-octadienyl)oxy]psoralen] are primarily responsible for the grapefruit effect, yet the exact mechanisms and roles that specific compounds play in this effect are still uncertain. In the current experiments freshly extracted grapefruit juice was separated into four fractions, consisting of raw finished juice (approximately 5% fine pulp), centrifugal retentate (approximately 35% fine pulp), centrifuged supernatant (<1% pulp), and coarse finisher pulp. The relative concentrations of furanocoumarins in each of these grapefruit juice fractions were measured by HPLC-MS. These measurements showed that the centrifugal retentate had the highest furanocoumarin content, containing 892 ppm of bergamottin, 628 ppm of 6',7'-dihydroxybergamottin, 116 ppm of 6',7'-Epoxybergamottin, 105 ppm of 7-geranyloxycoumarin, and approximately 467 ppm of furanocoumarin dimers. These high furanocoumarin concentrations make this fraction a useful starting material for preparative-scale isolations of these compounds. MS analysis of this furanocoumarin-enriched fraction provided evidence of additional furanocoumarins in grapefruit juice that remain to be fully characterized and evaluated for their roles in the grapefruit-drug interactions.